Sepsis and Septic Shock Guidelines

One of the main guidelines in sepsis is the Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock from 2012 (updating the 2008 guidelines).

Pocket Guide

Key recommendations and suggestions:

• Early quantitative resuscitation of the septic patient during the first 6 hrs after recognition (1C)
• Blood cultures before antibiotic therapy (1C)
• Imaging studies performed to confirm a potential source of infection (UG)
• Administration of broad-spectrum antimicrobials therapy within 1 hr of recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B)
• Infection source control with attention to the balance of risks and benefits of the chosen method within 12 hrs of diagnosis (1C)
• Initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1C)
• Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to acheive a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients) (1C)
• Fluid challenge technique continued as long as hemodynamic improvement, as based on either dynamic or static variables (UG)
• Norepinephrine as the first-choice vasporessor to maintain mean arterial pressure >/= 65 mm Hg (1B)
• Epinephrine when an additional agent is needed to maintain adequate blood pressure (2B)
• Vasopression (0.03 U/min) can be added to NE to either raise MAP to target or to decrease NE dose but should not be used as the initial vasopressor (UG)
• Dopamine is not recommended except in highly selected circumstances (2C)
• Dobutamine infusion administered or added to vasopressor in the presence of a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or b) ongoing signs of hypoperfusion despite acheiving adequate intravascular volume and adequate MAP (1C)
• Avoiding use of IV hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C)
• Hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B)
• Low tidal volume (1A) and limiation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS)
• Application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B)
• Higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C)
• Recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C)
• Prone positioning in sepsis-induced ARDS patients with a PaO2/FIO2 ratio of </= 100 mm Hg in facilities that have experience with such practicees (2C)
• Head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B)
• A conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C)
• Protocols for weaning and sedation (1A)
• Minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B)
• Avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C)
• A short course of neuromuscular blocker (no longer than 48 hours) for patients with early ARDS and a PaO2/FIO2 < 150 mm Hg (2C)
• A protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are > 180 mg/dL, targeting an upper blood glucose </= 180 mg/dL (1A)
• Equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B)
• Prophylaxis for deep vein thrombosis (1B)
• Use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B)
• Oral or enteral (if necessary) feedings, as tolerated, rathern than either complete fasting or provision of only IV glucose with the first 48 hrs after a diagnosis of severe sepsis/septic shock (2C)
• Addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 hours of intesive care unit admission (2C). 

Osteoporosis: Topic of the Day

The National Osteoporosis Foundation released an update to its Clinician's Guide to the Prevention and Treatment of Osteoporosis last year (April 2014). 

The current version (2014) was released April 1, 2014. The 2014 version of the Clinician’s Guide stresses the importance of screening vertebral imaging to diagnose asymptomatic vertebral fractures; provides updated information on calcium, vitamin D and osteoporosis medications; addresses duration of treatment; and includes an expanded discussion on the utility of biochemical markers of bone turnover and an evaluation of secondary causes of osteoporosis.

Osteoporosis Guidelines

Postmenopausal women and men age 50 and older

National Osteoporosis Foundation (2014) U.S. Preventative Services Task Force among other organizations

Postmenopausal women

 American Association of Clinical Endocrinologists (2010) – North American Menopause Society (2010)

Men

Endocrine Society (2012)

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Review of the 2014 NOF Clinician's Guide

• Approach to the diagnosis and management of osteoporosis
• Universal Recommendations 
• Pharmacotherapy (Who) and FDA indications
• Sequential and combination therapy
• Duration of treatment

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Dual‐energy Absorptiometry (DXA) Bone Density Testing: Indications

• NOF guideline
  • Women > 65 years old and men > 70 years old
  • Younger postmenopausal women, women in the menopausal transition, and men age 50‐69 years old with clinical risk factors for fracture • e.g., current smoker, low body weight, history of osteoporosis, low trauma fracture in a first‐degree relative
  • Adults who have a fracture after age 50 years
  • Adults with specific conditions or medications associated with bone loss
• Other – Women 50‐ 64 years old with FRAX overall fracture risk > 9.3% (USPSTF) – 

WHO Definition of Osteoporosis Based on Bone Mineral Density testing results:

• Normal 
  • BMD within 1 SD of the mean level for a young-adult reference population
  • T-score at -1.0 and above
• Lone Bone Mass (Osteopenia)
  • BMD between 1.0 and 2.5 SD below that of the mean level for a young-adult reference population
  • T-score between -1.0 and -2.5
• Osteoporosis
  • BMD 2.5 SD or more below that of the mean level for a young adult reference population
  • T-score at or below -2.5
• Severe or Established Osteoporosis
  • BMD 2.5 SD or more below that of the mean level for a young adult reference population
  • T-score at or below -2.5 with one or more fractures

Imaging Recommendations

• Vertebral Imaging recommended for women age 70 and older and all men age 80 and older if BMD T-score at the spine, total hip or femoral neck is </= -1.0
• Women age 65-69 and men age 70-79 if BMD T-score at the spine, total hip or femoral neck is </= -1.5
• Postmenopausal women and men age 50 and older with specific risk factors: low trauma fracture during adulthood (age 50), historical height loss of 1.5 inches or more (4 cm), prospective height loss of 0.8 inches or more (2 cm), or recent or ongoing long-term glucocorticoid treatment.

FRAX was developed to calculate a 10-year probability of a hip fracture and the 10-year probability of a major osteoporotic fracture (defined as clinical vertebral, hip, forearm or proximal humerus fracture). FRAX algorithm available at www.nof.org as well as at www.shef.ac.uk/FRAX.

FRAX is for postmenopausal women and men age 50 and older. In patients being pharmacologically treated for osteoporosis, clinical judgment must be use in interpreting results. No treatment in 2 years could be interpreted as untreated. Femoral neck BMD is preferred in calculating FRAX.

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Diagnosis of Osteoporosis (WHO Criteria) (Postmenopausal women and men >/= 50 years of age)

• T‐score at ‐1.0 or above  (SD) Normal
• T‐score between ‐1.0  and ‐2.5 (SD) - Low bone mass (Osteopenia)
• T‐score at or below ‐2.5 (SD) - Osteoporosis
• T‐score at or below ‐2.5 (SD) with one or more fractures - Severe or established osteoporosis SD = standard deviation

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Diagnosis of Osteoporosis (International Society for Clinical Densitometry 2007 Guidelines)*

• Z‐score above ‐2.0 (SD) “Within the expected range for age”
• Z‐score at or below ‐2.0 (SD) “Low bone mineral density for chronological age” or “Below the expected range for age” SD = standard deviation Premenopausal Women, Men < 50 Years of Age, and Children * These criteria are never used alone to diagnose osteoporosis in these populations

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RECOMMENDATIONS IN ALL PATIENTS:

Several interventions to preserve bone strength can be recommended to the general population. These include an adequate intake of calcium and vitamin D, lifelong participation in regular weight-bearing and muscle-strengthening exercise, cessation of tobacco use, identification and treatment of alcoholism, and treatment of risk factors for falling. 

Bone‐Healthy Lifestyle:

• Calcium - Recommended elemental calcium intake should be obtained ideally through dietary sources + supplements
• Age Group Recommended Daily Intake Maximum Daily Intake
  • 19-50 years 1000 mg
  • 50-70 years 2000 mg Men = 1000 mg Women = 1200 mg
  • ≥ 71 years 1200 mg

According to the updated 2014 National Osteoporosis Foundation guideline, intakes of calcium in excess of 1200 to 1500 mg per day could place a patient at increased risk for kidney stones, cardiovascular disease (CVD), and stroke. (J Bone Metab 2014;29:531‐3; J Bone Metab 2014;21:21‐8; Am J Clin Nutr 2011;94:270‐277)

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Vitamin D: This is the amount needed to maintain the majority of healthy patients within the sufficient range

• Age Group Recommended Daily Intake
  • National Osteoporosis Foundation (2014)
    • <50 years 400-800 units (4000 units max daily intake) 
    • ≥ 50 years 800-1000 units (4000 units max daily intake)
• Institute of Medicine (2010)
  • ≥ 71 years 800 units (4000 units max daily intake)
  • 51-70 years 600 units (4000 units max daily intake)
  • 19-50 years 600 units (4000 units max daily intake)

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When to Consider Drug Treatment

• History of (low trauma) hip or vertebral fracture
• T‐score - ‐2.5 at femoral neck, hip, or spine by central DXA
• Postmenopausal women and men 50 years of age if T‐score between –1 and –2.5 and 10‐year hip fracture probability of 3% or a 10‐year all major osteoporosis‐related fracture probability of 20%

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Bisphosphonates:  inhibit osteoclastic bone resorption and reduce osteoclast activity and beneficial effect on osteoblasts.

• Drug holidays are being considered for bisphosphonates to prevent which serious long‐term adverse effects 
• Show residual effects after discontuation
• Evidence for efficacy beyond 5 years is limited, whereas rare safety concerns become more common beyond 5 years. 
• Reasonable to discontinue after 3-5 years in patients who have a modest risk of fracture after the initial treatment period, but in high risk, continued treatment or alternative treatment should be considered.

Non-Bisphosphonates: produce temporary effects that wane with discontinuation.

Duration of Treatment and Drug Holiday

• Alendronate: Duration of treatment 5 years. Assessment for reinitiation: 1-2 years
• Risedronate: Duration of treatment 5 years. Assessment for reinitiation: 1 year
• Zoledronic acid: Duration of treatment 3 years. Assessment for reinitiation: 2-3 years

Denosumab Role in Therapy

• FDA osteoporosis indications
  • Postmenopausal women and men with high fracture risk (Osteoporosis fracture, multiple risk factors, can’t use other meds)
  • Androgen deprivation therapy for nonmetastatic prostate cancer
  • Adjuvant aromatase inhibitor for breast cancer
• AACE guideline – first line
• Increases BMD for at least 8 years
• Vertebral, hip, & nonvertebral fracture prevention
• Quicker reversal with medication discontinuation
• Adverse effects: Common adverse reactions (> 5% and diff placebo)
  • Back, shoulder, leg, and musculoskeletal pain – Increased cholesterol – Cystitis
  • Cases of MRONJ and atypical fractures

Raloxifene Role in Therapy

• FDA indications
  • Osteoporosis prevention and treatment
  • Postmenopausal women with osteoporosis and/or at high risk for invasive breast cancer
• AACE guideline –Second‐ and third‐line therapy
• Dose ‐ 60 mg daily
• Contraindications ‐ active or past history venous thromboembolism
• Precaution – risk for stroke
• Adverse effects – Vasomotor symptoms (hot flushes) – Leg cramps – Breast tenderness – Spotting – Venous thromboembolism – Box warning – fatal stroke

Teriparatide Role in Therapy

• FDA indications
  • Postmenopausal women at high risk for fracture
  • Men with primary or hypogonadal osteoporosis at high risk for fracture
  • Glucocorticoid‐induced osteoporosis
  • High fracture risk
    • Previous fracture
    • Extremely low BMD (T‐score < ‐3.5)
    • Multiple risk factors for fracture
  • Teriparatide Dose, Selection, and Common Adverse Effects
    • 20 mcg subcutaneously daily for 24 months
    • Once weekly injection in trials – ? Start antiresorptive agent before end of therapy
    • Contraindications – Skeletal muscle radiation, bone cancer, hypercalcemia, Paget’s disease
    • Common adverse effects
      • Orthostasis – first doses
      • Nausea, arthralgia, leg cramps
      • Hypercalcemia (check calcium at baseline)
      • Box warning ‐ osteosarcoma (animal data)

Calcitonin: Role in Therapy, Efficacy, Dose, and Adverse Effects

• FDA indication – osteoporosis treatment for women   5 years post menopause with low bone mass
• AACE guideline – fourth‐line therapy
• Only vertebral fracture prevention
• Dosing –Intranasal ‐ 200 units daily alternating nares
• Adverse effects –Nasal – rhinitis, epistaxis, irritation –Subcutaneous – pain, redness –Other – nausea, allergic response, backache, headache –FDA post‐marketing analysis for cancer risk

References:

• National Osteoporosis Foundation (2014)

• U.S. Preventive Services Task Force – calcium vitamin D (2013)

• Ann Intern Med 2013;158:691‐696

• U.S. Preventive Services Task Force – screening (2011) – www.uspreventiveservicestaskforce.org/uspstf/uspsoste.htm

• International Society for Clinical Densitometry (2013) – www.iscd.org/documents/2013/07/2013‐iscd‐official‐ positions‐adult.pdf

• American Association of Clinical Endocrinologists(2010)

• Endocr Pract 2010;16(Suppl 3):1‐37

• North American Menopause Society (2010) – www.menopause.org/docs/default‐document‐ library/psosteo10.pdf?sfvrsn=2

• Endocrine Society (2012) – J Clin Endocrinol Metab 2012;97:1802‐1822

CPOE Implementation: A Status Report

Back in 1999, the Institute of Medicine (IOM) published the article "To Err is Human: Building a Safer Health System," which focused on preventing adverse drug events (ADEs).

Computerized Physician Order Entry (CPOE) was touted as a tool to reduce ADEs. Subsequent studies pointed out how it would help prevent medication errors and improve patient safety.

The US government has pushed computerization, as well.

"To improve the quality of our health care while lowering its cost," President Barack Obama said back in January 2009, "we will make the immediate investments necessary to ensure that, within 5 years, all of America's medical records are computerized."

It has now been 6 years, and medical records are still not 100% computerized.

Implementation of CPOE has been slow due to its complexity and huge cost. To further entice hospitals to jump on board with electronic health records (EHR), the US Centers for Medicare and Medicaid Services (CMS) sends money to facilities that meet set goals.

EHR systems are not something that can be rushed, but for dollars, workarounds happen. There is also the threat of penalties if systems are not implemented.

As the EHR market has matured, the once-crowded field of vendors has narrowed significantly.

At the end of 2013, just 10 vendors accounted for about 90% of the hospital EHR market: Epic, MEDITECH, CPSI, Cerner, McKesson, Healthland, Siemens, Healthcare Management Systems, Allscripts and NextGen Healthcare, according to Becker's Hospital Review.

No CPOE standardization

CPOE systems are all different, so how are they compared? A hospital may have implemented a CPOE, but does that equate to a sufficient system? Do groups like Leapfrog take into account CPOE errors or just the percentage of usage by prescribers? Do we rate CPOE systems like we rate hospitals?

Data show vendor CPOE market share, but there are no rating systems to evaluate the systems after implementation, or even a list of hospitals that decided to change systems due to issues.

Limited medication profiles

Another issue with CPOE is its lack of a coherent view of a patient’s profile while entering medications. It is also difficult to verify orders without a comprehensive view of the medications that the patient is taking.

This lack of a full picture causes the user, whether prescriber or verifier, to rely on the software alone, rather than a comprehensive approach. Seeing the whole picture while entering and verifying orders would probably decrease errors.

Alert fatigue

When CPOE systems are used for other tasks aside from entering and verifying orders, there is more alert fatigue.

On the pharmacist verification end, it is common to see alerts of different significance with nothing to differentiate high importance from low. For example, the same type of alert may be used to discuss inventory, prior authorization, and other messages that take away from the verification role, even though many of these alerts previously happened at order entry.

Pharmacists should not have to think pharmacologically and pharmacokinetically about how a medication works along with alerts dealing with inventory, cost, and formulary status that once occurred at the front end. There should be a way to differentiate these alerts and have them fire at appropriate times, rather than during actual medication review. 

Tailoring the CPOE to be more user-friendly for the prescriber often comes at the expense of more frustration on the back-end with verification. For example, a CPOE may allow a prescriber to free type directions for medications taken irregularly (3 days a week, different strengths on different days), choose non-formulary medications rather than built-in CPOE formularies, and remove alerts that need to be seen at order entry.

In this way, verification becomes more of an order entry “fix” role that pulls attention from clinical aspects of verification.

CPOE software is also designed under the assumption that prescribers and verifiers are working in a quiet environment, but both sides are working in noisy environments. When a phone is ringing, a patient is yelling, and a nurse is asking a question, quick pop-up alerts may not be enough of a warning. Even the most focused individual will make mistakes.

More duplicate orders

The Journal of the American Medical Informatics Association published a study pre and post-implementation of a CPOE in an ICU and found that duplicate medication ordering errors increased after implementation (pre: 48 errors, 2.6% total; post: 167 errors, 8.1% total; p<0.0001).

Sometimes, there is a lack of integration between laboratory values, both inpatient and home medications, and other data or different modules that do not communicate smoothly.
 
Last but not least, if the staff is not happy with the CPOE software that is implemented, they are not going to use it as designed. - See more at Pharmacy TImes.

The Top Searched Medications of 2014

The Top Searched Medications of 2014

Interested in the top searches in medications in 2014? This year’s list includes:

1. Antibiotics: No, this is not a drug but a drug category; however I suppose capturing the whole category is OK. We have issues with antibiotic resistance, drives for antimicrobial stewardship, and drug-drug interactions. 

2. Adderall: Increased from #6 search last year though it’s been around for years. Adderall has spent the past 10 years in the top 10 of medication google searches.

3. Alprazolam: Same as Adderall has been searched enough to be in the top 10 for 11 years.

4. Ibuprofen: Who knew but I bet all the parents of kids are constantly looking up doses.

5. Steroid: This could capture creams, tablets, and parenteral.

6. Tramadol

7. Tylenol

8. Paracetamol: Another term for APAP 

9. Naproxen

10. Aspirin

11. Sildenafil: I wonder if online pharmacies are the reason? Privacy in purchasing.

12. Sertraline

13. Amoxicillin

14. Gabapentin

15. Cyclobenzaprine

16. Analgesic: Again a class of drugs that contain many specific ones on this list.

17. Fluoxetine

18. Bupropion

19. Omeprazole

20. Escitalopram

With mostly medications for pain, depression/anxiety, and infection the list captures usage as well. Cite top prescribed drugs in same year?

Cholesterol Guideline Changes

A whopping 13 million more Americans will now be taking statins due to the recent changes in the guidelines formulated by the American Heart Association and the American College of Cardiology (source:  NEJM).  The new guidelines released by the American Heart Association were released back last November.  

The new guidelines are taking a very different approach.  Rather than focusing on specific end targets for cholesterol, the guidelines focus more on risk and prevention of strokes and heart attacks.  They disregard the guideline that doctors should prescribe cholesterol-lowering drugs when a patient's LDL, or bad cholesterol, reaches a certain threshold — in recent years, above 130.  The guidelines also say everyone with known heart disease should be taking statins.

The guideline recommends statin therapy for the following groups:

• People without cardiovascular disease who are 40 to 75 years old and have a 7.5 percent or higher risk for having a heart attack or stroke within 10 years.  (According to a new risk calculator).
• People with a history of a cardiovascular event (heart attack, stroke, stable or unstable angina, peripheral artery disease, transient ischemic attack, or coronary or other arterial revascularization).
• People 21 and older who have a very high level of bad cholesterol (190 mg/dL or higher).
• People with Type 1 or Type 2 diabetes who are 40 to 75 years old.  The drugs are also recommended for younger adults if their LDL cholesterol is over 190.

(Just for reference the old guidelines, using a different calculator, prescribed statin use at a 10-year risk above 20 percent, along with an LDL-cholesterol reading above 130).

As far as side effects go:

• FDA's Guidelines

Ativan Drips and Precipitation

If you happen to run short of the lorazepam 2 mg/mL vials to compound your ativan drips, be mindful of the possibility of precipitation when using the lorazepam 4 mg/mL vials.  AHFS Drug Info states:

Precipitation-- The choice of commercial lorazepam concentration to use in the preparation of dilutions is a critical factor in the physical stability of the dilutions. Both the 2- and 4-mg/mL concentrations utilize the same concentrations of solubilizing solvents. On admixture, the solvents that keep the aqueous insoluble lorazepam in solution are diluted twice as much using the 4-mg/mL concentration than if the 2- mg/mL were used, resulting in different precipitation potentials for the same concentration of lorazepam. Care should be taken to ensure that the compounding procedure that is to be used for lorazepam admixtures has been demonstrated to result in solutions in which the lorazepam remains soluble.

Lorazepam concentrations up to 0.08 mg/mL have been reported to be physically stable, while occasional precipitate formation in admixtures of lorazepam 0.1 to 0.2 mg/mL has been reported. The precipitate has been observed in both containers and in administration set tubing.

In one case, a visible precipitate formed in a lorazepam 0.5-mg/mL admixture in sodium chloride 0.9% in a glass bottle.  However, a 0.5-mg/mL concentration may remain in solution longer if prepared from the 2-mg/mL concentration, yielding a higher concentration of organic solvents in the final admixture.

Concentrations of 1 and 2 mg/mL have been reported to be physically stable for up to 24 hours as well as concentrations below 0.08 mg/mL.

Concentrations in the middle range of 0.8 to 1 mg/mL may be problematic.  In one report, use of lorazepam 2 mg/mL to prepare lorazepam 1-mg/mL admixtures in dextrose 5% or sodium chloride 0.9% was acceptable but use of the lorazepam 4-mg/mL concentration to prepare the same solutions resulted in almost immediate precipitation.

Lorazepam solubility in common infusion solutions has been reported. Its solubility in sodium chloride 0.9% is approximately half that found in the other tested solutions. This result was attributed to the pH of the sodium chloride 0.9% (pH 6.3) being essentially the same as the isoelectric point of lorazepam (pH 6.4), where aqueous solubility would be the lowest. Dextrose 5% was the best diluent for lorazepam.

If you are a hospital or facility that mixes the middle range of 0.8mg to 1 mg/mL you have to be more mindful of other factors.  This is the reason I had no idea of this problem since other facilities where I have worked we mixed a much less concentrated solution.  I found out the validity of this information and wasn't too pleased.

The bottom line is that it would be nearly impossible for a pharmacist to know every single intricacies of different hospitals and compounding practices.  If knowledge like this is indeed something we should all 100%  know, then someone somewhere dropped the ball on training and/or education.  I am mostly wondering, how does your facility compound ativan drips?  What scenarios caused precipitation?

For more about this issue read here.

Bring on a Pharmacist... Please

WASHINGTON –  Federal health officials are alerting doctors to the recall of an injectable antibiotic made by B. Braun Medical, due to floating particles found in vials of the drug. The Food and Drug Administration posted the notice late Tuesday, warning health professionals that the company has recalled lot H3A7444 of its Cefepime for Injection USP and Dextrose Injection USP. Visible particles were found in a sample from the lot, including specs of metal, cotton fiber and hair.

The agency warned that using the drug could result in blood clots causing stroke, heart attack and other catastrophic problems.

The drug was distributed to hospitals, pharmacies and medical suppliers nationwide, according to the agency's release.

Patients experiencing health problems should contact their physician and report all issues to the company at 1-800-854-6851.

Hearing the newsanchor mispronounce cefepime threw me off.  Initially thought he was talking about some drug I had never heard of.  If news can bring on a Dr. Oz or the Doctors show, how about bringing in a pharmacotherapy specialist to discuss medications?

Should you be recommending a proton pump inhibitor (PPI) or H2-receptor antagonist (H2RA) for stress ulcer prophylaxis in critically ill patients?

We know that PPIs are better than H2RAs at raising intragastric pH, but we don’t know whether this higher pH value translates to superior clinical outcomes.  In fact, there is some debate whether a higher pH could actually cause problems, like nosocomial pneumonia or Clostridium difficile infection.  Given that clinically important GI bleeding has been associated with a high mortality rate (48.5% vs. 9.1% in non-bleeders), it seems that selecting the best agent for stress ulcer prophylaxis is an important decision. This hotly-debated topic, reinvigorated by the 2012 Surviving Sepsis Campaign Guidelines’ grade 2D recommendation in favor of PPIs, has again been examined with a recent meta-analysis by Alhazzani et al published in the March 2013 issue of Critical Care Medicine.

Actual .pdf of meta-analysis.

Of course, this is not the first meta-analysis to examine the topic.  In fact, three other meta-analyses have been published since 2009.  Here, here, and here. Naturally, the authors of this most recent meta-analysis claim that their statistical analysis was superior, they included more relevant trials, and they excluded more inappropriate trials to make this analysis a more pure, scientifically-valid view of the data.

This meta-analysis combined 14 randomized controlled trials with 1,720 total patients.  The analysis concluded that PPIs were associated with a reduction in clinically important upper GI bleeding (1.2% vs. 6.4%, NNT 19, RR 0.36, p=0.002) and overt upper GI bleeding (3.8% vs. 15.7%, NNT 9, RR 0.35, p<0.0001).  There was no difference in nosocomial pneumonia, ICU mortality, or ICU length of stay.

Is it time for famotidine and ranitidine to hang up their hat in the ICU?  The evidence from this meta-analysis appears compelling at first glance, but diving deep into the manuscript reveals some troubling issues.

First, the included trials were not comparing similar treatments of H2RAs.  Some trials used continuous infusions, some used once daily dosing, and one did not report dose at all.  It is scientifically questionable to pool a variety of different H2RAs with different dosing strategies together into a single group and categorize the treatments as being the same.

Second, the included trials did not have consistent definitions for “clinically important bleeding” and “overt bleeding”.  Some trials used very strict definitions where bleeding had to be confirmed with EGD, others has very loose criteria (eg, hemodynamic instability not explained by other causes), and some did not even provide definitions.  Indicative of the questionable criteria, 5 of the 12 included trials had an event rate of 0% in both arms, whereas one trial had an event rate as high as 31%.

Third, one must question whether the endpoint of “clinically important bleeding” is a surrogate or a clinically relevant outcome.  Given the questionable definitions and criteria used, a firm endpoint like ICU mortality would be a definitive approach to concluding a victor.  Unfortunately, there was no difference in ICU mortality demonstrated in this meta-analysis (17.5% PPI vs. 21.2% H2RA, p=0.91).

Given the paucity of high-quality data examining PPIs versus H2RAs for stress ulcer prophylaxis, it can be extremely temping to favor meta-analyses to find an answer to this compelling question.  The fallacy in this approach, however, is that you cannot take a multitude of poor-quality trials (many with fewer than 50 patients in the H2RA arm) and somehow combine the data into a valid, reliable, unbiased manuscript on which you base your clinical practice.

So how should we interpret this meta-analysis?  In my view, until better quality evidence comes out, there is no proven difference in the prevention of stress ulcer prophylaxis between PPIs and H2RAs.  The decision should be made based on formulary considerations (cost and availability), formulation considerations (ability to be crushed), the patient’s history of using a particular agent prior to admission, and potentially drug interactions (although I believe the PPI/omeprazole debate has not been concluded).

Sean P. Kane is a critical care clinical pharmacist and the author of ClinCalc.com -- an evidence-based website with clinical tools and calculators for medical professionals.

Nexium photo:  Photo credit: License Some rights reserved by Rennett Stowe

Guest Post: Pain Management - A Way Out of Addiction To Pain-Killers and Opiates

Pain is a natural process we all have to go through in life, physical pain being the most common type. Whether it be from the prick of a needle or the debilitating pain of rheumatism, such circumstances require appropriate management, otherwise it can critically affect one's lifestyle. The use of painkillers and opiates are typical in the medical field. Ranging from Hydrocodone to Morphine, these valuable tools are used to treat many different diseases and injuries, including ankle sprains, headaches, animal bites, etc. Though they are safe to use in controlled frequencies and amounts within the care and observation of medical institutions, things can go out of hand when measures proper care isn't taken. If this sound all too familiar to you, here's what you should know.

What is Addiction? To work your way out of painkiller and opiate addiction, you must first understand when you're in that actual state. There are many symptoms of addiction that anyone can recognize. They are somewhat of a gray matter, however, mainly because pain is a subjective experience. Since different patients have different thresholds for pain, it becomes complicated to know whether the drugs have failed to manage the patient's pain or whether the patient is lying in order to be administered more painkillers. Common signs of addiction include running out of a prescription early, telling your physician the prescription is lost, using multiple doctors to get pain medication, and borrowing pain medication from friends.

The Best Solution Withdrawing from painkillers and opiates may just be as difficult and consequential as withdrawing from stronger illegal drugs. For this reason, it is recommended that one enter an inpatient facility in order to take on this challenging process right. An inpatient detox facility can help you through the initial pains of detox. The first few days are usually the hardest and most demanding, as it causes chills, fever, muscle pain, nausea and vomiting, due to spontaneous withdrawal. The staff in this facility also will also help one to understand why they began using in the first place and how to avoid making the same mistakes again.

Other Options? If inpatient care is not an option, the next best way to withdraw safely and effectively from painkillers and opiates is to slowly but surely stop taking the substance. For many, stopping spontaneously only makes the process of withdrawal more complicated and escalates the chances of a relapse before one even has the opportunity to orient themselves.

Natural Pre-Emption One of the best ways to avoid addiction to dangerous substances is to head off the reasons for taking them in the first place. For instance, headaches are currently the most common form of pain in today's fast-paced lifestyle. Many factors lead to headaches, and they can commonly be dealt with by tuning in to what your body naturally requires (rest, reduction of stress, etc), instead of simply reaching for drugs.

Painkillers and opiates do have advantageous effects. However, make sure you practice only the pain management techniques prescribed by a doctor. Even if you think something's not working or not strong enough, never make an adjustment to your dosage without consulting a professional - and never, ever try any medication without a prescription. Not only is it illegal, it could have very dangerous side effects.

Mya Gilmore is a nurse who writes about health, nutrition and more at the Bow Creek & Bella Vista Recovery Centers.

All Things Vancomycin

Believe it or not, vancomycin was first isolated in the fifties from an isolate of dirt in the jungles of Borneo by a missionary. It is a naturally occurring antibiotic made by the soil bacterium Actinobacteria. The name vancomycin comes from the word vanquish.  Initially it was used as a sort-of last resort for penicillinase-producing strains of Staphylococcus aureus.  Today, vancomycin is one of the most widely used antibiotics for the treatment of serious gram positive infections involving methicillin-resistant S. aureus (MRSA). Years ago, early use of vancomycin was associated with several different types of toxicities including infusion related effects (Red Man Syndrome), nephrotoxicity (kidney), and possible ototoxicity (damage to ears).  It was determined later that the majority of these adverse effects were due to the early formulations that contained impurities; however, by that time, its use was decreased with the development of other penicillin-type medicines like methicillin, oxacillin, and nafcillin).  Thanks to MRSA, Vancomycin is making a huge comeback, or has been since the early 1980s.

On a side note, Red Man Syndrome is not an allergic reaction.  This can be managed with a histamine blocker or slowing down the infusion.  Can't tell you how many times I have seen this listed as an allergy to vancomycin on someone's profile.

In monitoring Vancomycin, trough serum concentrations are the most accurate method.  Typically draw the trough level prior to the fourth dose (steady-state).  Keep trough levels above at least 10 mg/L to avoid development of resistance.  For a pathogen with an MIC of 1 mg/L, the minimum trough concentration would have to be at least 15 mg/L.  For complicated infections, the optimal trough concentrations are 15-20 mg/L to improve penetration, increase optimal serum concentrations, and improve clinical outcomes.

How to dose?  Dosing vancomycin is a bit of an art, but start at 15-20 mg/kg using actual body weight.  Many hospitals encourage a maximum dose of 2 grams.  Definitely adjust dose in renal dysfunction.

Creatinine Clearance(based on Cockcroft and Gault and not eGRF)	Dose*
>60 ml/min	Uncomplicated Infections: 10-15 mg/kg q12h1  Serious Infections: Consider loading dose of 25mg/kg IV x1, followed by 15-20 mg/kg q8-12h (45-60mg/kg/day divided q12h or q8h)2
40-60 ml/min	10-15 mg/kg q12h-q24h
20-40 ml/min	5-10 mg/kg q24h
10-20 ml/min	5-10 mg/kg q24h-q48h
<10 ml/min	10 - 15 mg/kg IV loading dose x1; redose according to serum levels
Hemodialysis	15-20 mg/kg load, then 500 mg IV post HD only
CVVH	10-15 mg/kg q24h

* round dose to 250mg, 500mg, 750mg, 1g, 1.25g, 1.5g, 1.75g or 2g (maximum: 2gm/dose)

Higher total daily doses of vancomycin have been associated with nephrotoxicity

¹ For patients with uncomplicated infections requiring vancomycin, trough levels of 10-15 mcg/ml are recommended.

² For patients with serious infections due to MRSA (central nervous system infections, endocarditis, ventilator-associated pneumonia, bacteremia or osteomyelitis) , trough levels of 15-20 mcg/ml are recommended.

Vancomycin troughs are not recommended in patients in whom anticipated duration of therapy is short (≤ 3 days)

Trough levels are recommended for routine monitoring (for intermittent hemodialysis, a pre-dialysis level should be drawn). Trough levels should be obtained within 30 minutes before 4^th dose of a new regimen or dosage change.

Once weekly monitoring is reasonable in patients with stable renal function and clinical status. (Data supporting safety or prolonged troughs of 15-20 mcg/ml is limited.)

There is a great app out there I recommend called Vancomycin ClinCalc Full.  The author also has a website called ClinCalc you can check out to see if the dosing matches how your particular program wants you to do it.

I don't earn a dime for that link either, I just enjoy finding quality programs to work more efficiently.

I love Dr. Walter Crittenden, PharmD MD "An Infections Disease Compendium:  A Persiflagers Guide" on the iPad as well.

One of my biggest pet-peeves is when I hear someone say, "Oh I have blown their kidneys!" in regards to one serum creatinine level coming back higher.  Hey, let's wait until 2-3 consecutive high serum creatinine concentrations (increase of 0.5 mg/dL or 150% increase from baseline, whichever is greater) after several days before making such a claim.  Seriously.

And the "Rants and Screeds" of Dr. Crittenden, "Vancomycin is a shitty drug; mostly static, toxic, lousy pharmacokinetics, penetrates poorly into all tissues.  When compared to beta lactams, it is always worse."

Gotta love that!