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Archive for July, 2006

ABX – Empiric ABX for Severe Sepsis/Septic Shock

Written by phil

July 27th, 2006 at 3:11 am

Posted in Antibiotics

Surviving Sepsis Lecture

Written by phil

July 27th, 2006 at 12:21 am

Posted in Lecture Notes

Antibiotic Recommendations

Emergency Department Empiric Antibiotic Recommendations:

Pneumonia
Uncomplicated urinary tract infections in women
Complicated urinary tract infections
Intra-abdominal infections
Skin and soft-tissue infections
Severe Sepsis & Septic Shock

Restricted antimicrobials now stocked in the ED (but continue to require ID oversight):

Cefepime (Maxipime)
Ampicillin-Sulbactam (Unasyn)

• Daytime (9am- 6pm) call the Antimicrobial Assistance Program and request/notify of the need for either cefepime or ampicillin-sulbactam and order in IBEX.

• Off-hours (6pm-9am) order cefepime or ampicillin-sulbactam in IBEX. The “night time request for restricted antimicrobials” form no longer needs to be sent to pharmacy. Pharmacy will track use via IBEX.

• The IBEX chart must reflect the clinical indication for the restricted antimicrobial (see recommendations).

Antimicrobial Assistance Program: (ID pharmacists and ID physicians available for approvals and recommendations)

Pager 9407 (adult)
Pager 3737 (pediatrics)

NOTE !
If there is any delay in reaching an ID pharmacist or ID physician, call the pharmacy directly. A first dose will be released STAT when a patient needs a restricted antimicrobial emergently.

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Recommendations provided thanks to Dr. Nassisi
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2006 Antibiogram Highlights

Written by phil

July 15th, 2006 at 3:39 pm

Posted in Antibiotics

ABX – Complicated UTI

Men – Cystitis.

Ciprofloxacin 500 mg orally twice daily for 7 days.

OR

Levaquin 500 mg orally once daily for 7 days.

For men <40 years of age it is usually an STD and >40 years of age it is usually E. Coli. Urethritis must be considered in sexually active men less than 40 years of age: examination for penile ulcerations and urine diagnostic tests for Neisseria gonorrhoeae and Chlamydia trachomatis (GC Probe) are warranted in this age group. Avoid Nitrofurantoin and beta-lactams in men with cystitis or pyelonephritis, since they do not achieve reliable prostatic tissue concentrations and would be ineffective for occult prostatitis.

Men – Prostatitis

Ciprofloxacin 500 mg orally twice daily for 4 weeks.

OR

Levaquin 500 mg orally once daily for 4 weeks

Acute prostatitis is manifested with frequency, dysuria, and difficulty urinating with fever and a tender prostate. In the presence of urinary retention or obstruction, and high fever: AVOID digital rectal exam as it could lead to sepsis, in these cases consult Urology.

Men – Acute pyelonephritis

Levaquin 500 mg IV/po once daily 10-14 days

OR

Ciprofloxacin 400 mg IV twice daily for 10-14 days. (can switch to po 500 mg po bid)

All men with pyelonephritis should be evaluated for causative factors.

Pregnant Women – Cystitis

TMP-SMX (160 mg/800 mg) orally twice a day for 7 days (FDA Category C: AVOID in first trimester)

OR

Amoxicillin 500 mg orally twice daily for 7 days. (FDA Category B)

OR

Nitrofurantoin (Macrodantin) 100 mg four times a day for 7days (FDA Category B)

OR

Macrobid (the extended release-XR-form of nitrofurantoin) 100 mg twice a day for 7 days can be prescribed for outpatient use
only. (FDA Category B)

OR

Cephalexin 250 mg orally four times daily for 7 days. (FDA Category B)

Fluoroquinolones should be avoided in pregnancy. Pregnant women should have a follow-up urine culture performed one to two weeks after treatment to ensure that bacteriuria has been eradicated. Treat as outpatients as long as they do not have symptoms suggestive of pyelonephritis. Have a low threshold for hospitalization.

Pregnant Women – Acute pyelonephritis

Ceftriaxone 1 gram IV every 24 hours for 10-14 days.

In the Mount Sinai 2005 antibiogram for the ED, Ceftriaxone was effective against 97% of E.Coli Isolates.

Nursing Home patients

Ceftriaxone 1 gram IV every 24 hours (preferred)

OR

If multi drug resistant gram negative suspected or previously isolated: Cefepime 1 gram IV every 12 hours.

Risk factors for multi-drug resistant resistant gram negative: frequent hospitalizations (>3) within the past year, recent hospitalization in an acute setting in the past 3 month, spinal cord injury individuals with intermittent catheterization, patients with suprapubic catheters or indwelling urinary catheters. In the Mount Sinai 2005 antibiogram for the ED, Ceftriaxone was effective against 97% of E.Coli Isolates.

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The choice of antibiotic should be based on the antimicrobial sensitivity if available. Page the ID pharmacist (9407) or the ID fellow on call for antimicrobial assistance.
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Ref: Patterson T. Detection, significance, and therapy of bacteriuria in pregnancy. Update in the managed health care era. Infect Dis Clin North Am 1997 Sep;11(3):593-608.
Nicolle, L. A practical guide to the management of complicated urinary tract infection. Drugs 1997; 53:583.

Written by phil

July 15th, 2006 at 3:37 pm

Posted in Antibiotics

ABX – Intra-Abdominal Infections

Cholangitis OR Cholecystitis

Unasyn 1.5 grams IV every 6 hours

In obese patients, use Unasyn 3g.

Acute cholecystitis is primarily an inflammatory process, however secondary infection of the gallbladder can occur as a result of cystic duct obstruction and bile stasis resulting in cholangitis.

Uncomplicated Diverticulitis – No Recent Hospitalization*

Cefazolin 1gm IV every 8 hours + Flagyl 500 mg IV every 8 hours (recommended as first line based on Mount Sinai antibiogram)

OR

Levaquin 500 mg po once every 24 hours + Flagyl 500 mg po every 8 hours

In obese patients use Cefazolin 2g.

Community isolates of E.Coli are 89% sens to Cefazolin, but only 81% sens to Fluroquinolones as per 2005 ED antibiogram. Agents that are used to treat nosocomial infections in the intensive care unit should not be routinely used to treat community-acquired infections which are principally Gram negative rods and anaerobes (particularly E. coli and B. fragilis), using broader-spectrum antibiotics would contribute to the development of resistance.

Uncomplicated Diverticulitis – Recent Hospitalization*

Ceftriaxone 1 gm IV every 24 hours + Flagyl 500 mg IV every 6 hours (recommended as first line based on Mount Sinai antibiogram)

OR

Unasyn 1.5 grams IV every 6h.

In obese patients use ceftriaxone 2g instead of 1g or Unasyn 3g.

*Recent Hospitalization: Within the past three months or frequent hospitalizations (>3) within the past year.

Appendicitis – No Recent Hospitalization*

Cefazolin 1gm IV every 8 hours + Flagyl 500 mg IV every 8 hours

Community isolates of E.Coli are 89% sens to Cefazolin, but only 81% sens to fluroquinolones as per 2005 ED antibiogram.

Appendicitis – Recent Hospitalization*

Ceftriaxone 1 gm IV every 24 hours + Flagyl 500 mg IV every 6 hours (recommended as first line based on Mount Sinai antibiogram)

OR

Unasyn 1.5 grams IV every 6 hours.

*Recent Hospitalization: Within the past three months or frequent hospitalizations (>3) within the past year.

SBP in Cirrhotic Patients – Not on Furoquinolone Prophylaxis

Cefotaxime 2 g IV every 8 hours

Most cases of SBP are due to gut bacteria, such as Escherichia coli and Klebsiella. Dosing of cefotaxime 2 g intravenously every eight hours produces excellent ascitic fluid levels.

Written by phil

July 15th, 2006 at 3:36 pm

Posted in Antibiotics

ABX – Soft Tissue Infection

Cellulitis – Community acquired – Group A strep MSSA

Nafcillin 1–2 g every 4 h IV (Dicloxacillin 500 mg orally 4 times per day)

OR

Cefazolin 1 g every 8 h IV (Cephalexin 500 mg orally 4 times per day)

OR

Clindamycin 600 mg every 8 h IV (Clindamycin 300–450 mg orally 4 times per day).

Most cases of cellulitis are caused by Group A strep unless there is a portal of entry such as furuncles, carbuncles, abscesses or penetrating trauma in which case staph aureus is probably the cause. CDC data reveals that 99.5% of Group A strep strains remain susceptible to clindamycin, and 100% are susceptible to penicillin.

Cellulitis – Community acquired – MRSA suspected*

TMP-SMZ 2 double-strength tablets orally twice
per day.

OR

Clindamycin 600 mg every 8 h IV (Clindamycin 300–450 mg orally 4 times per day).

*Risk factors for Community acquired MRSA= Injection drug users, Homeless populations, Children, Jail and prison inmates, Military recruits, Native populations, Men who have sex with men, contact sports, HIV+ patients. Clindamycin has excellent antistaphylococcal activity, but there is the potential for emergence of inducible resistance to clindamycin if erythromycin resistance is present.

Cellulitis – Nosocomial – MRSA suspected*

Vancomycin 30 mg/kg/day IV every 12 hours.

*Risk Factors for Nosocomial MRSA= frequent hospitalization, nursing home resident, dialysis, immunocompromised.

NECROTIZING SKIN AND SOFT-TISSUE INFECTIONS

Clues: (1) pain disproportionate to physical findings, (2) violaceous bullae, (3) cutaneous hemorrhage, (4) skin sloughing, (5) skin anesthesia, (6) rapid progression, and (7) gas in tissue Surgical intervention is the major therapeutic
modality in cases of necrotizing fasciitis, also CT scanning and measurement of the serum creatine kinase (CK). The rationale for clindamycin is based on in vitro studies demonstrating both toxin suppression and modulation of cytokine (i.e., TNF) production.

Necrotizing Fasciitis

Ampicillin-sulbactam 1.5 g IV every 6 hours (3g if >100 Kg) + clindamycin 600–900 mg every 8 h iv

OR

Imipenem/cilastatin 1 g every 6–8 h iv

Monomicrobial infection caused by group A streptococcus (Streptococcus pyogenes) or clostridium. Predisposing factors: blunt trauma, varicella (chickenpox), injection drug use, a penetrating injury, surgical procedures, childbirth, burns, nonsteroidal antiinflammatory drugs.

OR

Mixed polymicrobial infection caused by aerobic and anaerobic bacteria. Predisposing risk Factors: immunocompromised, surgical procedures, diabetes, peripheral vascular disease, co-morbidities, decubitus ulcers, and spontaneous mucosal tears of the gastrointestinal or gastrourinary tract (i.e., Fournier gangrene).

Bites – Animal and Human

Ampicillin-sulbactam 1.5–3.0 g IV every 6h
(Amoxicillin/clavulanate 500/875 mg twice per day)

Bites – Animal and Human with PCN allergy

Clindamycin 600–900 mg IV every 8 h + Levaquin 500 mg IV once daily

Pasteurella species are isolated from 50% of dog bite wounds and 75% of cat bite wounds. Human bites reflect oral flora of the biter and tend to be more serious: strep viridans, Eikenella corrodens, Fusobacterium species, peptostreptococci, and Prevotella. Both Ampicillin-sulbactam and Fluroquinolones have activity against Pasteurella.

Diabetic Foot – Mild soft tissue infections AND no previous antibiotics

Nafcillin 1–2 g every 4 h IV
(Dicloxacillin 500 mg orally 4 times per day)

OR

Cefazolin 1 g every 8 h IV
(Cephalexin 500 mg orally 4 times per day)

OR

Clindamycin 600 mg every 8 h IV (Clindamycin 300–450 mg orally 4 times per day).

In mild diabetic soft tissue infections: therapy should be directed against aerobic gram positive organisms particularly, coagulase-negative staphylococci and S. aureus.

Diabetic Foot – Moderate soft tissue infections AND/OR previous antibiotic exposure

Ampicillin-sulbactam 1.5–3.0 g IV every 6h
(Amoxicillin/clavulanate 500/875 mg PO twice per day)

OR

Clindamycin 600–900 mg IV every 8 h + Levaquin 500 mg IV once daily

Initial oral broad-spectrum antimicrobial therapy should be directed at gram-positive, gram-negative, and anaerobic organisms.
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Ref. Stevens DL, Bisno A, Chambers H et al. Practice Guidelines for the Diagnosis and Management of Skin and Soft-Tissue Infections Clin Infect Dis 2005; 41:1373–406
IDSA guidelines for the diagnosis and treatment of diabetic foot infections: Clinical Infectious Diseases 2004; 39:885-910.

Written by phil

July 15th, 2006 at 3:36 pm

Posted in Antibiotics

ABX – Uncomplicated UTI in Women

Cystitis – with the following:

  • Has no history of allergy to Sulfa drug
  • Has not been on antibiotics, especially TMP-SMX, in the past three months for any reason.
  • Has not been hospitalized recently

TMP-SMX (160 mg/800 mg) orally twice a day for 3 days

E. coli is the causative pathogen in approximately 80 to 85 percent of episodes of acute uncomplicated cystitis. Staphylococcus saprophyticus is responsible for most other episodes. E. Coli resistance to TMP-SMX is about 10 % in the northeast US.
There is no apparent benefit in extending therapy with TMP-SMX or a fluoroquinolone past three days, and adverse reactions are more common in patients treated with longer regimens. This also appears to apply to women over the age of 65 years
Allergy to TMP-SMX

Cystitis with Risk factors for TMP-SMX resistance including:

  • Moderate to severe symptoms
  • Women who might find it difficult to seek additional care if their symptoms do not significantly improve over a short time: homelessness or lack of health insurance.

Ciprofloxacin 250 mg orally twice a day for 3 days

OR

Nitrofurantoin (Macrodantin) 100 mg four times a day for 7days

OR

Macrobid (the extended release-XR-form of nitrofurantoin) 100 mg twice a day for 7 days can be prescribed for outpatient use only.

The antimicrobials currently recommended for cystitis, TMP-SMX, nitrofurantoin, and fluoroquinolones, have excellent activity in vitro against S. saprophyticus.
The prevalence of resistance to nitrofurantoin among E. coli is less than 5 percent.
For patients with allergies to both TMP-SMX and/or Fluroquinolones, another option is Keflex 250 mg po four times a day for 7 days, although compliance with such a regimen might be an issue.

Pyelonephritis

Fever (>38ºC), flank pain, costovertebral angle tenderness, and nausea or vomiting suggest upper tract infection and warrant more aggressive diagnostic and therapeutic measures.

If outpatient therapy for mild pyelonephritis is a possibility in a patient tolerating oral medications/diet, would treat for 10 days with a fluroquinolone.

Ceftriaxone 1 g IV once a day

OR

Ciprofloxacin 500 mg po twice a day (or 400 mg IV twice a day if unable to take oral)
OR

Levaquin 500 mg orally once a day (or IV if unable to take po)

In the Mount Sinai 2005 antibiogram for the ED, Ceftriaxone was effective against 97% of E.Coli Isolates. E. Coli resistance to the fluoroquinolones remains well below 5 percent in most studies.

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Note: Patients with urethritis and vaginitis also may complain of dysuria, thereby presenting a diagnostic challenge. Urethritis caused by Neisseria gonorrheae or Chlamydia trachomatis is relatively more likely to be present if in the
setting of a sexually transmitted disease (STD).

Written by phil

July 15th, 2006 at 3:35 pm

Posted in Antibiotics

ABX – Pneumonia

Outpatient Previously healthy – No Recent Antibiotic Therapy

Doxycycline 100 mg orally twice a day for 7 days

OR

Levaquin 750 mg orally once a day for 5 days

OR

Z-Pack (Azithromycin 500 mg orally once on day 1 then 250 mg every day for day 2 to 5)

Doxycycline is active against 90%-95% of strains of S. pneumoniae, also active against H. influenzae, atypical agents, and category A bacterial agents of bioterrorism. Generally well tolerated and inexpensive. Macrolides active against most common pathogens, including atypical agents. Macrolide resistance is reported for 20%-30% of Streptococcus pneumoniae.

Outpatient Previously Healthy – Recent Antibiotic Therapy

Z-Pack + Amoxicillin-clavulanate 2 g orally twice a day for 7 days.

OR

Z-pack+ Amoxicillin 1 g orally three times a day for 7 days

OR

Levaquin 750 mg orally once a day for 5 days

Antibiotic for treatment of any infection within the past 3 months. Recent use of a fluoroquinolone should dictate selection of a non- fluoroquinolone regimen, and vice versa. Compared with amoxicillin, amoxicillin-clavulanate spectrum in vitro includes B-lactamase producing bacteria, such as most H. influenzae, methicillin-susceptible Staphylococcus aureus, and anaerobes. Lacks activity against atypical agents, also is more expensive and has more gastrointestinal intolerance, when compared with amoxicillin. High dosages amoxicillin (3 g/day) required to achieve activity against >90% of S. pneumoniae. Lacks activity against atypical agents and B-lactamase producing bacteria.

Outpatient with Comorbidities* – No Recent Antibiotic Therapy**

Levaquin 750 mg orally once a day for 5 days

Outpatient with Comorbidities* – Recent Antibiotic Therapy**

Z-pack + Amoxicillin-clavulanate 2 g orally twice a day for 7 days.

OR

Levaquin 750 mg once a day for 5 days

* Comorbities = Malignancy, COPD, Diabetes, CHF, Renal or Liver Disease

** Recent Antibiotics = Antibiotic for treatment of any infection within the past 3 months. Recent use of a fluoroquinolone should dictate selection of a non- fluoroquinolone regimen, and vice versa.

Suspected Aspiration with Infection

Amoxicillin-clavulanate 2 g orally twice a day for 7 days

OR

Clindamycin 600 mg orally three times a day for 7 days Coverage of oral flora.

Inpatient Non-ICU

Community acquired Levaquin 750 mg orally once daily

OR

Z-pack + Ceftriaxone 1 g IV once daily

If multi drug resistant gram negative suspected or previously isolated or if recently hospitalized: Cefepime 1 gram IV every 12 hours.

Recent antibiotics: Antibiotic for treatment of any infection within the past 3 months. Recent use of a fluoroquinolone should dictate selection of a non- fluoroquinolone regimen, and vice versa. In obese patients use ceftriaxone 2g instead of 1g. Levaquin is active against >98% of S. pneumoniae strains in the United States, including penicillin-resistant strains. Concern for abuse with risk of increasing resistance by S. pneumoniae. Active against H. influenzae, atypical agents, methicillin-susceptible S. aureus. Expensive. Ceftriaxone is active in vitro against 90%-95% of S. pneumoniae, also active against H. influenzae and methicillin-susceptible S. aureus.

Aspiration with infection
Clindamycin 600 mg orally every 8 hours + Levaquin 750 mg orally once daily Coverage of oral flora.

ICU – Not recently hospitalized

Ceftriaxone 1g IV once daily + Azithromycin 500 mg po or IV once daily

For patients with CAP in the ICU, always cover S. pneumoniae and Legionella. Legionella must be treated for 21 days. Patients hospitalized for pneumonia in the ICU should have 2 pretreatment blood cultures and endotracheal aspirate sent for Gram stain and culture. In obese patients use ceftriaxone 2g instead of 1g.

ICU – Recently hospitalized

Cefepime 1g IV every 12 hours + Azithromycin 500 mg po or IV once daily

Cefepime retains excellent activity against s. pneumoniae but also covers more resistant gram negatives. In obese patients use Cefepime 2g instead of 1g.

Nursing Home Resident2

ICU – Hospitalized or ICU bound

Cefepime 1 g IV every 12 hours + Azithromycin 500 mg po or IV once daily

Elderly patients of long-term care facilities have been found to have a spectrum of pathogens that most closely resemble late-onset hospital acquired pneumonia and ventilator associated pneumonia. Coverage against More resistant gram negatives, including pseudomonas should be provided.

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1. Update of Practice Guidelines for the Management of Community-Acquired Pneumonia in Immunocompetent Adults. Mandell LA, Bartlett JG, Dowell SF, File TM, Musher D, and Whitney C. Clin Infect Dis 2003;37:1405-1433.
2. Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Health-care-associated Pneumonia?American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med 2005;171:388-416.

Written by phil

July 15th, 2006 at 3:33 pm

Posted in Antibiotics

ED Protocol for Administration of PROPOFOL to Tracheally Intubated Adult Patients

1. Purpose of this Protocol
The purpose of this protocol is to ensure the safe and effective use of PROPOFOL in the ED. This protocol is not intended to replace the full prescribing information but to supplement that information with further details from practical experience. Because of the potential for adverse events and the differences between PROPOFOL and other agents used for sedation, the appropriate use of PROPOFOL in the ED is critical.

PROPOFOL is an intravenous sedative hypnotic agent that is indicated for the induction and maintenance of anesthesia and for sedation during monitored anesthesia care (MAC). It is also indicated for use in the ED as a sedative drug and has proved to be effective for ED sedation in Neuro/Head Trauma patients. It is an appropriate agent for short term sedation (i.e., 6-48 hrs) of ED patients in whom moderate to deep sedation is required followed by relatively rapid wake up time for purposes of assessment of neurological status while awaiting for a bed in the hospital.

2. Clinical Pharmacology
A. Pharmacokinetics
The proper use of PROPOFOL requires an understanding of the disposition and elimination characteristics of PROPOFOL.

The pharmacokinetics of PROPOFOL are well described by a linear three-compartment model with compartments representing the plasma, rapidly equilibrating tissues, and slowly equilibrating tissues. After an IV bolus dose, there is rapid equilibration between the plasma and the highly perfused tissue of the brain. Plasma levels initially decline rapidly because of high metabolic clearance and rapid distribution into the tissues. Distribution accounts for about half of this decline. However, distribution is not constant over time but decreases as body tissues equilibrate with plasma and become saturated.

Discontinuation of the recommended doses of PROPOFOL after the maintenance of anesthesia for approximately one hour, results in a prompt decrease in blood propofol concentrations and rapid patient awakening.

Significant tissue stores of propofol are accumulated after longer infusions (10 day infusion) resulting in a slowed reduction in circulating propofol. As a result, the time to awakening is increased. However, even after long-term administration, rapid awakening within 10 to 15 minutes will occur if the dosage of PROPOFOL is titrated daily to achieve only the minimum effective therapeutic concentration. If higher than necessary infusion levels have been maintained over an extended period, propofol will be redistributed from fat and muscle to the plasma. The return of propofol from peripheral tissues will slow recovery.

The large contribution of distribution (about 50%) to the fall of propofol plasma levels following brief infusions means that after very long infusions (at steady state), about half the initial rate will maintain the same plasma levels. Failure to reduce the infusion rate in patients receiving PROPOFOL for extended periods may result in excessively high blood concentrations of the drug. Titration to clinical response and daily evaluation of sedation levels are especially important during long duration use of PROPOFOL infusion for ED sedation.

B. Pharmacodynamics
The pharmacodynamic properties of PROPOFOL depend on the therapeutic blood concentrations. Steady-state blood concentrations of PROPOFOL generally are proportional to infusion rates, especially within an individual patient.

With longer infusions, the return to the plasma of the drug accumulated in the tissues causes plasma levels to fall more slowly. Thus titration to clinical response of sedation level is important during use of PROPOFOL for ED sedation. Should patients stay in the ED over a 12 hour period, daily evaluation of sedation is important as well.

Undesirable side effects, such as cardiorespiratory depression, are likely to occur at the higher blood levels that result from bolus dosing or rapid increase in the infusion rate. An adequate interval (3 to 5 minutes) between dosage adjustments is necessary to assess the drug’s effects.

3. PROPOFOL differs from other sedative hypnotic agents

The pharmacokinetic and pharmacodynamic properties of PROPOFOL differentiate it from other sedative hypnotic agents. Because PROPOFOL is unlike other sedatives, you must be familiar with the full prescribing information.

PROPOFOL is highly lipophilic. After injection into the bloodstream, PROPOFOL is rapidly cleared from the blood by both distribution into fatty tissues and rapid metabolic clearance via the liver to inactive metabolites.

Although the terminal elimination half-life of PROPOFOL is 1 to 3 days, the rapid metabolic clearance and redistribution into fatty tissues result in a short duration of clinical effect. The sedative effects of PROPOFOL typically dissipate within 5 to 10 minutes after the infusion is discontinued. Thus patients receiving PROPOFOL can be titrated relatively quickly from low levels of sedation to high levels of sedation and vice versa based on clinical need.

With longer infusions, the return to the plasma of the drug accumulated in the tissues causes plasma levels to fall more slowly.

After very long infusions (at steady state), about half the initial infusion rate will maintain the same plasma levels. Thus titration to clinical response and daily evaluation of sedation level are important during use of PROPOFOL infusion for ED sedation, especially of long duration. Excessively high blood concentrations of the drug may result from failure to reduce the infusion rate in patients receiving PROPOFOL for extended periods.

The vehicle (emulsion carrier) for PROPOFOL is essentially Intralipid® 10% (Abbott Laboratories) which also contains 0.005% disodium edetate to retard the rate of growth of microorganisms in the event of accidental extrinsic contamination. However, PROPOFOL is not an antimicrobially preserved product under United States “pharmacopeia (USP) Standards and can still support the growth of microorganisms. Therefore, strict aseptic technique must be adhered to. Aseptic handling methods are discussed on the PROPOFOL label and prescribing information (see below).

The pharmacokinetics of PROPOFOL do not appear to differ with respect to a patient’s sex or the presence of chronic hepatic cirrhosis or chronic renal impairment. The effects of acute hepatic or renal failure have not been studied.

Characteristics of PROPOFOL
Rapid onset of effect because the drug easily crosses the blood-brain barrier (see Clinical pharmacology). Intravenous injection of a therapeutic dose of propofol produces hypnosis rapidly with minimal excitation, usually within 40 seconds from the start of an injection.
Rapid termination of sedation (see Clinical pharmacology).
Resedation has not been seen after the infusion is discontinued if the drug has been carefully titrated.
Can decrease the dose requirements for many other medications, including antihypertensive agents, opioids, muscle relaxants, and lipid supplements.

4. Indications for use of PROPOFOL Injectable Emulsion in the ICU
PROPOFOL is indicated for use only in intubated, mechanically ventilated adult patients. It should be administered only by persons who are skilled in management of critically ill patients and trained in cardiovascular resuscitation and airway management.

PROPOFOL can be used whenever continuous sedation is needed to control anxiety and stress responses. Pain can be treated with relatively small amounts of analgesics. Sedation is achieved independently by titrating the PROPOFOL infusion

PROPOFOL is particularly beneficial in the following clinical situations:
Patients requiring continuous sedation who need to be awakened predictably for either central nervous system (CNS) assessments or weaning from ventilator.
Patients who are agitated and asynchronous with the ventilator.
Patients requiring deep sedation for diagnostic procedures.
Ventilator-dependent patients who require nighttime sedation only in order to maintain an adequate sleep-wake cycle.
Patients with delirium tremens refractory to other GABAergic medications.
Patients fully supported by mechanical ventilation who require short term sedation.
Patients refractory to other sedative agents.

Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of PROPOFOL required for sedation.

5. Patients who should NOT receive PROPOFOL Injectable EmulsionPROPOFOL is contraindicated in:
Patients known to be hypersensitive to the drug or its components (soybean oil, egg lecithin, glycerol, and disodium edetate).
Patients in whom sedation is contraindicated.

PROPOFOL is not recommended for use in:
Patients who are not intubated and mechanically ventilated.
Patients who are pregnant or nursing.

PROPOFOL should be used with caution in:
Patients with hyperlipidemia as evidenced by increased serum triglycerides or serum turbidity.
Patients who are hypotensive, hypovolemic, or hemodynamically unstable.
Patients who are predisposed to zinc deficiency, such as those with burns, diarrhea, and/or major sepsis. In these patients, the need for supplemental zinc should be considered during prolonged therapy with PROPOFOL.
In patients at risk for renal impairment, urinalysis and urine sediment should be checked prior to initiation of sedation and then monitored on alternate days during sedation.

6. Practical considerations
This section describes some practical considerations that critical care personnel should note before using PROPOFOL for the first time in ED sedation.

PROPOFOL is not like other drugs used for ED sedation. For example, sedation with midazolam typically is initiated using a bolus injection, followed by either repeat bolus injections or a continuous infusion to maintain sedation. Bolus dosing of PROPOFOL can produce hypotension and cardiorespiratory depression.

It is recommended that sedation with PROPOFOL be initiated with an infusion of 10 mcg/kg/min, and titrated up in 5 to 10 mcg/kg/min increments every 5 to 10 minutes until the desired level of sedation is achieved. Bolus administration should proceed with caution at the time infusion is begun in order to attain an adequate level of sedation within 5-10 minutes because incremental increasing of infusion alone may require 45 – 60 minutes. It is recommended that a bolus of between 0.5-2 mg/kg be given. The PROPOFOL infusion rate for maintaining sedation depends on the individual patient’s condition and age, patient type (e.g., postsurgical or medical), concomitant drug therapy, and the level of sedation desired. Infusion rates of 5 to 100 mcg/kg/min or higher may be required to maintain sedation with PROPOFOL.

PROPOFOL and Analgesic Requirements
Although there are reports of reduced analgesic requirements when PROPOFOL is administered, most patients require opioids for analgesia during maintenance of ED sedation. When using PROPOFOL for ED sedation, you must evaluate the level of pain being experienced by the patient and administer the appropriate amount of analgesic. When pain is adequately controlled, PROPOFOL infusion can be titrated to achieve the desired level of sedation.

Dosages of PROPOFOL should be reduced in patients who have received large doses of opioids. As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time.
Avoid Waking the Patient Too Quickly.
The wake-up time seen with PROPOFOL is faster than that of other sedative agents.

Because of the rapid clearance of PROPOFOL, abrupt discontinuation of a patient’s infusion may result in rapid awakening of the patient with associated anxiety, agitation, and resistance to mechanical ventilation, making weaning from mechanical ventilation difficult. It is therefore recommended that administration of PROPOFOL be continued in order to maintain a light level of sedation throughout the weaning process until 10 to 15 minutes before extubation, at which time the infusion can be discontinued.

When the PROPOFOL infusion is abruptly discontinued, the plasma levels of the drug decrease rapidly. The wake-up can occur so quickly that the patient may awaken abruptly in pain or to great environmental disorientation. Physicians and nurses may misinterpret the patient’s reaction as agitation caused by the drug. The patient’s reaction, however, is an appropriate response to the sudden influx of stimuli occurring during the transition from deep sedation to rapid, clearheaded awakening.

To avoid the potential problems associated with abrupt awakening, you should not interrupt the PROPOFOL infusion until patient awakening or a change in the level of sedation is deemed necessary.

Two scenarios where this is important are:
The infusion vial of PROPOFOL is inadvertently allowed to run dry (assuming that, as with midazolam or an opioid, the patient is unlikely to move or begin awakening for 30 minutes or more).
A physician or nurse abruptly stops the PROPOFOL infusion to awaken the patient for a physical examination or extubation.

In the first example, the problem can be avoided by ensuring that a second vial of PROPOFOL is immediately available. (The patient may wake up within as little as 5 minutes once the infusion stops, so reinitiating the infusion promptly is critical to ensure uninterrupted sedation.)

In the second example, the problem can be avoided by titrating the infusion rate down so that the patient awakens slowly. A procedure for awakening the patient for an examination or weaning from a ventilator is described below:
Adjust the infusion rate to achieve a light level of sedation.
For patients maintained at a Ramsay score of 3 or higher (see Appendix), decrease the infusion rate in 5- to10-mcg/kg/min increments at 10- to 15-minute intervals until a Ramsay score of 2, or the desired level of light sedation, is achieved.
Once the patient has reached a lightly sedated level, determine the level of orientation that is appropriate for the patient. For example, if the patient can attain full consciousness, gently wake the patient, talk to the patient, and allow the patient to become oriented to the surroundings.
Once the patient is oriented, discontinue the infusion. Within 10 to 15 minutes, the patient usually will be completely awake and clearheaded (assuming that the patient can achieve full consciousness).
After completing the evaluation of sedation level, titrate to a deeper level of sedation (if required) by increasing the infusion rate in 5- to 10-mcg/kg/min increments at 10- to 15-minute intervals.

Titration Is Important
ED sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension. Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of PROPOFOL required for sedation. The administration of PROPOFOL should be initiated as a continuous infusion and changes in the rate of administration made slowly (>5 minutes) in order to minimize hypotension and acute overdosage.

PROPOFOL facilitates titration because of its pharmacokinetic profile.

Many currently available sedatives are given by bolus injection. If the desired effect is not achieved after 30 minutes or more, the physician or nurse may administer more or less drug the next time. This intermittent bolus procedure often is considered “titrating” the sedative agent.

In contrast, the more rapidly acting vasopressors, such as sodium nitroprusside, are titrated slowly by increasing or decreasing the infusion rate and watching the cardiac monitors for the almost real-time effect. Within minutes, a vasopressor can be titrated to the exact response desired.

You should think of PROPOFOL in the same way as a potent vasopressor:
PROPOFOL should be bolused with extreme caution and careful attention to blood pressure.
PROPOFOL can be titrated within minutes to the desired effect.
PROPOFOL is rapidly cleared by the patient.

Rapid clearance of the drug means that:
The sedative effect can be raised or lowered within minutes with good control.
The patient recovers quickly from effects of PROPOFOL.
The nursing staff must ensure that the vial does not run out.

The speed and convenience of this level of titratability may not be readily apparent unless you understand the pharmacokinetics of PROPOFOL. For example, you need to wait 5 to 10 minutes between dose rate adjustments before the maximal effect is achieved (at which time a further dose adjustment can be made).

7. Initiating sedation with PROPOFOL
To minimize hypotension and avoid acute overdose, you should initiate PROPOFOL slowly using upward titration of a continuous infusion and careful bolus administration.

The dosage of PROPOFOL and rate of infusion must be individualized according to the patient’s condition, age, concomitant CNS drugs (e.g., opioids), blood lipid profile, and vital signs. During the first 24 to 48 hours, the PROPOFOL dosing requirement may gradually increase because of the dissipating effects of previously administered general anesthetics, other sedatives, or opioid analgesics.

DOSING GUIDELINES
Initiate the PROPOFOL infusion at 10cg/kg/min.
Increase the infusion rate in 5- to 10-mcg/kg/min increments every 5 to 10 minutes until the desired level of sedation is achieved.
Wait at least 3-5 minutes between dosage adjustments to allow for onset of maximal sedative and hemodynamic effects.
Monitor patients for early signs of significant hypotension or cardiovascular depression.
Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be susceptible to hypotension.
Hypotension and cardiovascular depression can be managed by decreasing or discontinuing the PROPOFOL infusion and/or administering IV fluids and/or administering vasopressor therapy.

The initiation dose requirements of PROPOFOL may be reduced in patients with intramuscular or intravenous premedication, particularly with opioids (eg, morphine, meperidine, and fentanyl) and combinations of opioids and sedatives (eg, benzodiazepines, barbiturates, etc). These agents may increase the anesthetic or sedative effects of PROPOFOL and may also result in more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output.

Bolus Dosing
The use of a bolus injection of PROPOFOL is only permitted when performed in a controlled setting and continuous observation of the patient’s state of consciousness and blood pressure is assured. An infusion induction method (upward titration of a continuous infusion) is recommended to minimize hypotension.

8. Maintaining sedation with PROPOFOL
Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of PROPOFOL required for sedation.

Maintenance dosages of PROPOFOL must be individualized and titrated to clinical response. The infusion rate depends on the individual patient’s condition and age, patient type (e.g., post-surgical or medical), concomitant drug therapy, and the desired level of sedation.
Most patients can be maintained with 5 to 50 mcg/kg/min or higher of PROPOFOL.
Patients recovering from the effects of general anesthesia or deep sedation and those who have received large doses of opioids may require lower maintenance dosages of PROPOFOL.
Patients in the ED and those who have fully recovered from the residual effects of general anesthesia or previous deep sedation induced by other drugs may require infusions of 50 mcg/kg/min or higher to maintain adequate sedation. These higher rates of administration may increase the likelihood of hypotension.

Patients who require more than 24 hours of continuous PROPOFOL infusion should be awakened daily. This daily evaluation of sedation level should be performed during maintenance to ensure that the patient is receiving the minimum dose of PROPOFOL required for sedation.

During maintenance infusion, you should monitor the patient’s vital signs, including blood pressure, heart rate, and if available, cardiac output and pulmonary capillary wedge pressure. If mild hypotension develops during titration, decrease the infusion rate of PROPOFOL. If clinically significant hypotension or cardiovascular depression occurs, discontinue vasodilator therapy (if applicable), administer intravenous fluids or vasopressor therapy, and discontinue the PROPOFOL infusion.

Once the patient has achieved an adequate level of sedation and is hemodynamically stable, you can maintain that rate of PROPOFOL infusion, except when titration is required for wake-up physical or neurologic assessment, family visits, or nursing care. You can sedate the patient more deeply during the evening hours or when the patient undergoes unpleasant procedures.

Determining the Minimum Maintenance Dose
Patients receiving maintenance infusions of PROPOFOL should be awakened daily to assess their respiratory and neurologic functions. These evaluations of sedation level are needed to ensure that the patient receives the lowest effective dose of PROPOFOL and that the patient’s pain is adequately managed.

Evaluation of level of sedation and assessment of CNS functions should be carried out daily throughout the maintenance to determine the minimum dose of PROPOFOL required for sedation.

9. Discontinuing or modifying the rate of infusion with PROPOFOL Injectable EmulsionThe PROPOFOL infusion should be discontinued or the rate of administration reduced:
If significant hypotension develops.
If unacceptably high triglyceride levels develop.
When sedation is no longer needed.
When the daily evaluation of sedation level is performed.
When the patient is extubated.

Because of the rapid clearance of PROPOFOL, abrupt discontinuation of a patient’s infusion may result in rapid awakening of the patient with associated anxiety, agitation, and resistance to mechanical ventilation, making weaning from mechanical ventilation difficult. It is therefore recommended that administration of PROPOFOL be continued in order to maintain a light level of sedation throughout the weaning process until 10 to 15 minutes before extubation, at which time the infusion can be discontinued.
Weaning from the Ventilator
The following procedure should be used when a patient who is sedated with PROPOFOL is weaned from a ventilator:
Discontinue concomitants, opioids, and paralytic agents (if applicable).
Gradually decrease the PROPOFOL infusion rate until the patient reaches a light level of sedation.
After the patient has been fully weaned from mechanical ventilation and meets all other extubation criteria, discontinue the PROPOFOL infusion 10 to 15 minutes before extubation.

10. Handling and administration

PROPOFOL Injectable Emulsion is a single-use, parenteral product that is formulated in a white, oil-in-water emulsion. The formulation also contains soybean oil (100 mg/mL), glycerol (22.5 mg/mL), egg lecithin (12 mg/mL), and disodium edetate (0.005%). The PROPOFOL vehicle is essentially Intralipid® 10%. Therefore, many of the handling, drug compatibility precautions, and administration line procedures used for Intralipid are applicable to PROPOFOL.

Strict aseptic technique must always be maintained during handling. PROPOFOL is a single-use parenteral product which contains 0.005% disodium edetate to retard the rate of growth of microorganisms in the event of accidental extrinsic contamination. However, PROPOFOL can still support the growth of microorganisms, as it is not an antimicrobially preserved product under USP Standards. Accordingly, strict aseptic technique must still be adhered to. Do not use if contamination is suspected. Discard unused portions as directed within the required time limits. There have been reports in which failure to use aseptic technique when handling PROPOFOL was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

When PROPOFOL is administered directly from the vial, strict aseptic techniques must be followed. The vial rubber stopper should be disinfected using 70% isopropyl alcohol. A sterile vent spike and sterile tubing must be used for administration. As with other lipid emulsions, the number of IV line manipulations should be minimized. Administration should begin promptly and must be completed within 12 hours after the vial has been spiked. The tubing and any unused portions of the PROPOFOL must be discarded after 12 hours.

If PROPOFOL is transferred to a syringe, or other container before administration, or if a PROPOFOL prefilled syringe is used, the syringe(s) or container(s) should be labeled with the date and time the PROPOFOL container was opened. Administration should begin promptly and be completed within 6 hours. The PROPOFOL should be discarded and the administration lines changed after 6 hours.

Rare cases of self-administration of PROPOFOL by health care professionals have been reported, including some fatalities. PROPOFOL should be managed to prevent the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting.
Summary of Handling Procedures for PROPOFOL
Use aseptic technique
Strict aseptic techniques must be followed when handling PROPOFOL. It is not an anti-microbially preserved product under USP Standards.
The vial rubber stopper should be disinfected using 70% isopropyl alcohol, and a sterile vent spike and sterile tubing must be used for administration.
As with other lipid emulsions, the number of IV line manipulations should be minimized. Administration should commence promptly and must be completed within 12 hours after the vial has been spiked for direct administration. The tubing and any unused portion of PROPOFOL must be discarded after 12 hours.
If PROPOFOL is transferred to a syringe or other container before administration, the handling procedures for General Anesthesia/MAC Sedation should be followed, and the product should be discarded and administration lines changed after 6 hours.
Inspect the drug for particulate matter and/or discoloration before administration.
Do not use if there is emulsion separation.
PROPOFOL should not be administered through a filter with a pore size of [less equal]5 microns, unless it has been demonstrated that the filter does not restrict the flow of PROPOFOL and/or cause the breakdown of the emulsion. Filters should be used with caution and only where clinically appropriate. Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.
Administration Procedures
You can administer PROPOFOL through a central line or a peripheral infusion line. Two procedures are available for administering PROPOFOL.

Direct infusion: The 50-mL or 100-mL infusion vials (which contain 10 mg/mL of PROPOFOL) can be used for direct infusion. A sterile vent spike and sterile tubing must be used. IV line manipulations should be minimized. Administration should begin promptly and must be completed within 12 hours after the vial has been spiked. The tubing and any unused portions of the drug must be discarded after 12 hours.

Transfer before infusion: If you transfer PROPOFOL to a sterile syringe or other container, or use a prefilled syringe, label the syringe or container with the date and time. The syringe or container and the tubing should be replaced every 6 hours.
Use of Infusion Devices
You can administer PROPOFOL using a volumetric or syringe pump. The type of device is less important than ensuring that the nursing staff is familiar with the equipment.

11. Compatibility
Dilution Prior to Administration:
PROPOFOL® (propofol) Injectable Emulsion is provided as a ready-to-use formulation. However, should dilution be necessary when PROPOFOL is diluted prior to administration, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL, because it is an emulsion. In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

Administration with Other Fluids:
Compatibility of PROPOFOL with the coadministration of blood/serum/plasma has not been established. PROPOFOL has been shown to be compatible when administered with the following intravenous fluids.
5% Dextrose Injection, USP
Lactated Ringers Injection, USP
Lactated Ringers and 5% Dextrose Injection
5% Dextrose and 0.45% Sodium Chloride, USP
5% Dextrose and 0.2% Sodium Chloride, USP
Drug Interactions
PROPOFOL dose requirements may be reduced in patients receiving concomitant opioids or a combination of opioids and sedatives. These agents may increase the sedative effects of PROPOFOL and may also result in more pronounced decreases in blood pressure or cardiac output.

Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension. Patients should be monitored for early signs of significant hypotension and/or cardiovascular depression, which may be profound.

12. Adverse events
Like other potent drugs, PROPOFOL has been associated with adverse events.

Hypotension was causally related in 26% of patients receiving bolus doses of PROPOFOL for ED sedation. In most cases, the decrease in blood pressure responded to fluid or vasopressor administration and/or adjustment or discontinuation of PROPOFOL.

Other causally related adverse events include hyperlipidemia, decreased cardiac output, bradycardia, and respiratory acidosis during weaning from a ventilator. Adverse events occurring rarely but probably casually related were green urine, agitation, and decreased lung function.

Because PROPOFOL is an oil-in-water emulsion, it should be used with caution in patients with lipid metabolism disorders, such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis. Elevations in serum triglycerides can occur when PROPOFOL is administered for extended periods. Patients at risk for hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity.

Studies to date, in patients with normal or impaired renal function have not shown any alteration in renal function with PROPOFOL. However, in patients at risk for renal impairment, urinalysis and urine sediment should be checked before initiation of sedation and then monitored on alternate days during sedation.

Overdosage
If overdosage occurs, you should immediately discontinue the PROPOFOL infusion. Overdosage can be avoided by slowly titrating the infusion.

Extravasation
As with any IV drug, extravasation into surrounding tissues has occurred with PROPOFOL. However, extravasation has not been associated with tissue necrosis. It can be managed with local care, such as elevation of the affected site to reduce swelling. PROPOFOL rarely causes phlebitis.

Appendix. Determining the level of sedation
Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of PROPOFOL required for sedation.

Determining the appropriate level of sedation can be facilitated through the use of sedation scales. Sedation scales can improve patient care by improving communication among ICU personnel. Staff members can refer to specifically defined levels of sedation when discussing their patients.
Various types of sedation scales exist. The best sedation scale is one that is convenient to use and is used consistently by all members of the department. In the absence of a preestablished sedation scale, you may consider using the Ramsay scale or a modified Ramsay scale:
Ramsay Scale
Patient anxious and agitated, or restless, or both.
Patient cooperative, accepting ventilation, oriented, and tranquil.
Patient asleep; brisk response to light glabellar tap or loud auditory stimulus.
Patient asleep; sluggish response to light glabellar tap or loud auditory stimulus.
Patient has no response to light glabellar tap or loud auditory stimulus but does respond to painful stimulus.
Patient does not respond to painful stimulus.
Modified Ramsay Scale
Patient anxious, agitated, or restless.
Patient cooperative, oriented, and tranquil.
Patient responds to commands only.
Patient responds to gentle shaking.
Patient responds to noxious stimulus.
Patient has no response to firm nailbed pressure or other noxious stimuli.

Appendix II. Lipid profile of PROPOFOL Injectable Emulsion
The PROPOFOL contains soybean oil (100 mg/mL), glycerol (22.5 mg/mL), and egg lecithin (12 mg/mL). One milliliter of PROPOFOL contains approximately 0.1 g of fat (1.1 kcal). Other sources of dietary intake, particularly Intralipid®, must be adjusted to compensate for the amount of lipid infused during PROPOFOL administration.

You should note on the patient’s chart the kcal equivalent of PROPOFOL being administered and ensure that the patient’s lipid nutritional supplement (eg, Intralipid) is reduced by an equivalent amount if the PROPOFOL infusion is likely to be continued for more than 24 hours..
Because PROPOFOL is an oil-in-water emulsion, it should be used with caution in patients with lipid metabolism disorders, such as primary hyperlipoproteinemia, diabetic hyperlipemia, and pancreatitis. Elevations in serum triglycerides can occur when PROPOFOL is administered for extended periods. Patients at risk for hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity.

Written by phil

July 12th, 2006 at 4:47 pm

Posted in ED Guidelines