Eastvold Pearl #27 - Superficial thrombophlebitis in the lower extremity

Hey guys,

Been a while, and have 2 more coming.  

Superficial thrombophlebitis (ST), aka superficial vein thrombosis

--

Thrombosis of superficial veins has long been considered benign, and deemed a separate entity from venous thromboemolism (VTE)

-- However, multiple studies illustrate a significant association with VTE (DVT and PE).

-- When patient with ST (diagnosed clinically, no ultrasound) are thoroughly evaluated, the degree and the extent of clot are underestimated 75% of the time.  Further, such patients are found to have co-existent DVT or PE 25% of the time and/or rapidly progress to DVT 10% of the time.  

---- Teaching point: get ultrasounds on all clinical superficial thrombophlebitis

-- The risk factors for ST and VTE are the same, and many argue that ST should be treated the same as VTE.  

-- In general,

anticoagulate (as you would for DVT) the patient if they have known clotting risk factors, greater than 5 cm of clot, or clot < 5 cm within the sapheno-femoral or sapheno-popliteal junction.

-- Another way to think about it is that a superficial vein thrombosis is a manifestation of a systemic clotting cascade gone awry.  To even further simplify things, seems pretty pathologic to have any blood vessel clot; ahh hello, you are clotting off blood vessels.

Below is my treatment algorithm on ST in the lower extremity.

Feedback always welcome.

Josh

References

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278049/#

    CHEST 2012 guidelines

Eur J Vasc Endovasc Surg 2005; 29:10-17. 

J Vasc Surg 2003; 37:834-8. 

Thromb Haemost 2001 ;86:452-63.

* Full anticoagulation with [a] lovenox 1 mg/kg BID (or 1.5 mg/kg QD) for at least 5 days and until coumadin is therapeutic for at least 24 hours. [b] Xarelto or rivaroxaban15 mg BID for the first 3 weeks, then 20mg daily for at least 3 months.  If lifelong anticoagulation planned, would recommend lovenox/coumadin.  2nd reoccurrence consider lifelong anticoagulation but refer to CHEST guidelines for specific permutations. A study by Schulman found a second DVT indicated a need for lifelong anticoagulation and it didn’t matter whether the DVT was provoked or unprovoked.  However, provoking factors vary in their risk of recurrence; surgery patients have the lowest risk of recurrence.  Patients with unprovoked or idiopathic thrombosis or multiple recurrences with lower risk provoking factors will get long‐term anticoagulation. 

** History of DVT or PE, active malignancy (recommend solely lovenox, d/w oncologist), hypercoagulable state.  Other risk factors that warrant consideration of systemic anticoagulation include male gender without varicose veins, history of superficial thrombophlebitis, recent surgery, involvement of saphenous vein, and severe symptoms.

*** Lots of variability in dosing. 

  -- Lovenox: [a] 40 mg daily SC x 4 weeks per CHEST guidelines, [b] 1 mg/kg BID SC x 10 days then 1 mg/kg QD x 20 days per Belgian Society on Thrombosis and Haemostasis. 

  -- Fondaparinux 2.5 mg SC QD x 30-45 days

  -- Xarelto – current trial comparing 10 mg PO QD vsfondaparinux.  Xarelto approved for DVT.  Would consider using if 1st time on anticoagulation given PO form and no need for INRs, but would discuss with PCP before committing to lifelong use of Xarelto.

****

Deep veins = superficial femoral vein, common femoral vein, deep femoral vein, popliteal vein, anterior tibial vein, posterior tibial vein, peroneal vein.

Superficial veins = Greater saphenous vein, small saphenous vein

Novel Anti-coagulants

A brief rundown of the players:

Dabigatran (Pradaxa) is a direct thrombin inhibitor, FDA approved in October 2010 for the prevention of CVA in patients with Afib.  In December 2011, the FDA initiated an investigation into reports of higher than expected rates of serious bleeding events.  Rates of dyspepsia and GI bleed are also concerning, and a small but significant increase in MI has been shown in safety outcome data from multiple trials.

Rivaroxaban (Xarelto) is a direct Factor Xa inhibitor, FDA approved July 2011 for DVT prophylaxis, and in November 2011 for prevention of CVA in patients with Afib.

Apixaban (Eliquis), another direct Factor Xa inhibitor, will likely be FDA approved in June 2012 for prevention of CVA in patients with Afib. 

This journal club examined the 3 major studies published in NEJM used to support the use of these novel anticoagulants in the prevention of CVA in patients with Afib.  Interestingly, these drugs are struggling when studied in ACS; APPRAISE-2 (study of apixaban + antiplatelet therapy after ACS) was stopped early in 2011 due to increase in major bleeding without significant reduction in recurrent ischemic events.  One other general note:  in all three of these studies, ICH (the bleeding complication that counts) was significantly less with the study drug as compared to warfarin.  All 3 of these drugs do ok in these non-inferiority studies-the important question is how they will perform in the real world, and it may be several years before safety conclusions and community effectiveness data give us the answer.

1.  Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009;361(12):1139-1151.  (RE-LY)

Dabigatran 150mg BID or 110mg BID (blinded) vs Dose adjusted warfarin (unblinded)

Randomized, noninferiority trial of 18,113 patients, median follow-up 2 years.

Condition: AF within 6 months prior to randomization + 1 risk factor for CVA.  Use of                antiplatelets acceptable.  Mean CHADS2 score 2.1.  Intention to treat.

Primary endpoint: Stroke or systemic embolism

• Warfarin 1.7%
• Dabigatran 110mg 1.5% (p=0.34)
• Dabigatran 150mg 1.1%   (p<0.001 for superiority)

Major Bleeding

• Warfarin 3.4%
• Dabigatran 110mg 2.7% (p=0.003)
• Dabigatran 150mg 3.1% (p=0.31)

ICH

• Warfarin 0.74%
• Dabigatran 110mg 0.23% (p<0.001)
• Dabigatran 150mg 0.3% (p<0.001)

Conclusion: Lower dose dabigatran similar to warfarin for preventing stroke/systemic embolism and caused less major bleeding than warfarin.  Higher dose dabigatran superior to warfarin for preventing stroke with similar rates of major bleeding to warfarin (trade off with dosing between benefit and bleeding).  Both doses of dabigatrin with significantly less ICH than warfarin.  Significantly higher rate of GI bleeding in higher dose dabigatran group as compared with warfarin.

Comments:  Tony-higher discontinuation rate with dabigatran, likely from dyspepsia rates.  What happens with the effectiveness of these drugs in the real world (external validity) when people don’t take them due to side effects, and there is no monitoring such as INR to reinforce compliance?  Also likely to see less of a difference between the drugs in motivated patients on warfarin with very well controlled INRs.  In real world, INR is maintained in therapeutic range only about 55% of the time.  You can improve warfarin safety and effectiveness if you use point of care monitoring and have motivated patients.  Brad-bottom line, concern about increased MI and GI bleed rates, and no easy reversal agent.

2.  Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. New England Journal of Medicine. 2011;365(10):883-891.  (ROCKET)

Rivaroxaban 20mg QD vs Dose adjusted Warfarin

Randomized double blind, noninferiority trial of 14,000 patients, median follow-up 707 days.

Condition: AF within 6 months prior to randomization + at least 2 risk factors for CVA.  Mean          CHADS2 score 3.5.

Primary endpoint: Stroke and systemic embolism

• Warfarin  2.4%
• Rivaroxaban 2.1% (ITT p=0.12 for superiority, p<0.001 for noninferiority)

Major Bleeding

• Warfarin 3.4%
• Rivaroxaban 3.6% (p=0.58)

ICH

• Warfarin 0.7%
• Rivaroxaban 0.5% (p=0.02)

Conclusion:  Rivaroxaban non-inferior to warfarin in the prevention of stroke/systemic embolism with no significant difference in major bleeding events and less ICH.

Comments:  Mark-patients in this study with higher CHADS2 scores-more like our patients.  Also noted the increased risk for thrombotic events after stopping rivaroxaban.  This is also something seen with clopidogrel (Plavix).  Brian noted the heavily subsidized authors. Three statistical analyses used in this study:  intention to treat, per-protocol and as treated safety analyses.  Superiority was achieved only in the as treated safety analysis.  It seems like a lot of data torturing to find a way to demonstrate superiority.

Statistics Rant about noninferiority studies.  We commonly read superiority studies-attempts to show that drug A is better than drug B.  Why do a noninferiority study?  It’s a logical choice when you can’t use a placebo arm, and want to show drug A is as “good as” drug B.  Also, choosing the noninferiority margin, or how close the results for drug A need to be to drug B in order to conclude that they are similar, is arbitrary.   Pick a margin, and if you’re dealing with FDA approval, you just need to pick a margin that the FDA will swallow in order to approve your drug.  For the apixaban study, if apixaban was shown to be at least 50% as good as wafarin, it was judged noninferior.  In general the requirements for noninferiority studies are much more lax than for superiority studies, making them attractive to Big Pharma.  Also, in the end, if you able to demonstrate and report superiority, your results looks even better.  As far as analyzing results, in randomized studies trying to demonstrate superiority, intention to treat (ITT) is the best approach.  With non-inferiority studies, it’s actually preferable to do both ITT and per-protocol analyses, as per-protocol analyses bias against demonstrating significant differences (is a stronger analysis).  When in doubt though, as Erik always stresses, look at effect size (number needed to treat, absolute risk reduction), the comparison between benefits and harms, and expense…not statistics, and certainly not p values.

3.  Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine. 2011;365(11):981-992.  (ARISTOTLE)

Apixaban 5mg BID vs Dose adjusted Warfarin

Randomized double blind noninferiority trial of 18,201 patients, median duration of followup                1.8 years.  Mean CHADS2 score 2.1.

Condition: AF within 6 months prior to randomization + at least 1 risk factor for CVA

Primary endpoint: Stroke or systemic embolism

• Apixaban 1.3%
• Warfarin 1.6% (p<0.001 for noninferiority, p=0.01 for superiority)

Major Bleeding

• Apixaban 2.1%
• Warfarin 3.1% (p<0.001)

ICH

• Apixaban 0.2%  
• Warfarin 0.5% (p<0.001)

Conclusion: Apixaban superior to warfarin in preventing stroke/systemic embolism with less major bleeding and lower rates of ICH.

Comments:  Paarul-questioned the costs of these agents.  Paarul and Pikul both felt the drug is promising, but have concerns about external validity, as there were significant inclusion/exclusion criteria.  Dabigatran costs 8 $/day, warfarin is 30 cents.  Need to factor in costs of INR testing, and as Mary pointed out, also costs of bridging with enoxaparin (Lovenox) if INR subtherapeutic.  Christine pointed out that the study stressed relative risk reduction, which can sound good, but is less appropriate than using absolute risk reduction.  Kelly wondered about the outcomes of the patients who bled-not discussed in the paper.  Harwood pointed out that although results superior to warfarin, small effect size:  NNT to prevent stroke/embolism 303, NNT to prevent a major bleed 104, NNT to save a life 238, and outside of carefully monitored study setting, real world effect size will likely be even less.

In my humble opinion, this is the strongest study of the three.  Then again, apixaban isn’t even FDA approved yet-unlike iPhones, there are potentially big downsides to being the early adopter for new drugs…meaningful safety conclusions are still years in the future.

BONUS!!  AVERROES - Apixaban in Patients with Atrial Fibrillation (this was a background article, but interesting as it compared Apixaban to ASA; relevant for patients who aren’t candidates for warfarin)

Apixaban 5mg BID vs ASA

5,600 patients

Condition: AF within 6 months prior to randomization + 1 risk factor for CVA

Primary endpoint: Stroke and systemic embolism

• ASA 3.9%
• Apixaban 1.7% (p<0.001)

Major Bleeding

• ASA 1.2%           
• Apixaban  1.4% (p=0.33)

ICH

• ASA 0.3%           
• Apixaban  0.4% (p=0.83)

Conclusion: Apixaban superior to aspirin with similar rate of major bleeding and ICH. Study stopped early due to benefit of apixaban over aspirin.

Pediatric IVF

Background:  Our current intravenous fluid (IVF) orders for pediatric patients follow an equation first published in 1957 (Holliday and Segar).  Electrolyte composition of IVF are based on average sodium content in low solute infant formula, with the untested assumption that oral requirements translate to a safe and appropriate IV solution.

Over time, case reports of iatrogenic hyponatremia in pediatric patients have been described, some leading to permanent neurologic impairment or death.  The hyponatremia is attributed to the use of hypotonic IVF such as 0.45 NS and 0.2NS.  The mechanisms are not fully elucidated, but likely are related to the temporarily high arginine vasopressin (AVP) levels seen in children hospitalized with many common disorders (asthma, infection, post-op, dehydration, etc), and an impaired clearance of electrolyte-free water.   Proponents of the status quo cite concerns about isotonic fluids leading to hypernatremia, hypertension, interstitial fluid overload and tissue damage from extravasation.

In 2007, the National Patient Safety Agency in the UK warned against the use of hypotonic IVF fluids in children, followed by similar warnings by the Institute for Safe Medication Practices in Canada in 2008 and the United States in 2009, yet many hospitals continue to use hypotonic IVF for their pediatric patients.

Article #1:

Montanana PA, Alapont M, Ocon AP et al. The Use of Isotonic Fluid as Maintenance Therapy Prevents Iatrogenic Hyponatremia in Pediatrics: A Randomized, Controlled Open Study,Pediatr Crit Care Med 2008;9:589 –597. 

In this non-blinded RCT, 128 PICU patients received either isotonic IVF (NaCl = 140 mEq/L) or hypotonic IVF (NaCl < 100 mEq/L).  Patients were followed for 24 hours, with electrolytes, glucose and BP measured at 0, 6, and 24 hours.  Baseline Na levels were similar in the two groups.  The primary outcome was hyponatremia (Na < 135) at 6 and 24 hours.   All eligible patients consented to be in the study (whoah, what’s going on with informed consent in Spain…and Australia in article 3-also 100% compliance!).   They did lose a number of patients, mostly because IVF were no longer required, but 8 patients discontinued the study due to hyponatremia.  At 24 hours, 20.6% of the hypotonic IVF group were hyponatremic, compared to 5.1% in the isotonic IVF group:  NNH (number needed to harm) with hypotonic fluids = 7.  There was no significant difference in adverse events or hypernatremia between the 2 groups.

Statistics Rant:  this study included a Bayesian analysis, which is worth a comment.   In a nutshell, there are two types of probability:  Bayesian and Frequency.  Frequentists rely on objective probabilities defined through well defined random experiments….think p values.  Bayesians interpret probability using their degree of belief in a hypothesis.  It’s more of a “how do we feel” about the statistics, rather than an arbitrary “p < 0.05 = truth”.   Many current journals are getting away from p values entirely.  A large effect size, combined with prior knowledge about the topic, can be more persuasive than a statistically significant p value in isolation.  Bayesians are all about pre-test and post-test probability; how does additional new information change your view of the likelihood of an event?

Discussion:  McKean brought up the excellent point that the study is not blinded, and therefore open to confounders.  It would also be preferable to use clinical, or patient oriented outcomes, rather than surrogate markers like sodium level, but clinical complications are going to be rare in this situation.  Although the number of patients with moderate or severe hyponatremia was low, they were all in the hypotonic fluid group and this is potentially more clinically relevant.

Article #2:

Choong K, Arora S, Cheng J et al. Hypotonic Versus Isotonic Maintenance Fluids After Surgery for Children: A Randomized Controlled Trial. Pediatrics 2011:128;857-864.

In this blinded study 258 post-op kids either received hypotonic (0.45NS) or isotonic (0.9NS) IVF for 48 hours.  Baseline characteristics in the two groups were similar.  Primary outcome was acute hyponatremia, defined as Na < /= 134.   Secondary outcomes included severe hyponatremia (Na < /= 129 or symptomatic), hypernatremia (Na >/= 146), and adverse events attributable to fluid choice or sodium level.   The risk of hyponatremia was significantly greater in the hypotonic group (40.8% vs 22.7 %; RR: 1.82 [95%CI:1.21-2.74]).  Eight patients in the hypotonic group developed severe hyponatremia as compared with 1 patient in the isotonic group.  In Harwood’s view, this is a study of 9 kids with severe hyponatremia (the most clinically concerning patients), and all but one received hypotonic fluids.  The risk of hypernatremia was not significantly different between the two groups, nor was the rate of adverse events.   NNT with isotonic IVF to prevent one case of hyponatremia = 6.

Discussion:   As Jess mentioned, there was a safety officer who alerted physicians if predetermined Na levels were met.  If electrolyte values were persistently abnormal, physicians could change the study solution to an open label IVF.   More patients in the hypotonic group were changed to open label IVF, with hyponatremia being the most commonly stated reason for the change.  This methodology likely decreased the rate of harmful outcomes and diluted the magnitude of the primary outcome (anticipate more harm and even more significance in the outcomes if the above safety choices hadn’t been made).

Article #3:

Neville KA, Verge CF, Rosenberg AR et al. Isotonic is Better than Hypotonic Saline for Intravenous Rehydration of Children with Gastroenteritis: a Prospective Randomised Study.Arch Dis Child 2006;91:226–232. 

The final study evaluated dehydrated children diagnosed with acute gastroenteritis.  In this study, a total of 102 children with acute gastroenteritis (AGE) received either D2.5 0.9NS or D2.5 0.45NS for 4 hours, with electrolytes measured in both blood and urine at 0 and 4 hours.  Results were analyzed according to whether patients started the study with a normal Na or if they began hyponatremic (Na < 135).  Physicians chose between two different rehydration rate protocols.  Patients were similar at baseline except for a higher rate of baseline hyponatremia in the isotonic fluid group.  The primary outcome was the change in serum sodium at 4 hours.  Thirty-six percent of the children were hyponatremic at the start of the study, and these patients were more likely to have been ill longer than patients with baseline normal serum sodiums.   The IV infusion rate did not affect the change in serum sodium, which is important as proponents of hypotonic fluids have argued that the rate rather than the type of IVF determines the risk of hyponatremia.  At 4 hours, in the hypotonic fluid group patients initially hyponatremic did not demonstrate a significant change in serum sodium, but patients initially normonatremic had a small drop in serum sodium.  In the isotonic group, at 4 hours those initially hyponatremic had a small increase in serum sodium, while those initially normonatremic had overall unchanged serum sodiums.  In other words, isotonic fluids appeared to prevent hyponatremia and did not cause any cases of hypernatremia.

Discussion:  Beau pointed out that this is a non-blinded study, but it did look at a “hard” outcome, serum sodium, that shouldn’t have been affected by blinding.  He also mentioned that the study did not address complications, length of stay, etc, and did not specify prior interventions such as anti-emetic administration.   As Jim Maletich discussed, this really was only a four-hour study, although for the subset of patients followed longer, the few cases of hyponatremia identified were all in the hypotonic fluid group.  Urine biochemical analysis reiterated Harwood’s point:  kids can handle sodium, but they aren’t good at handling (excreting) free water. 

Bottom line consensus from the group:  it’s time to change our practice.  Except for rare situations when children present with profound hypo or hypernatremia (for example patient with DI), the IVF of choice is 0.9NS, usually with KCl and dextrose added after any necessary initial resuscitation boluses have been given.  It’s the medically appropriate choice, should be financially equivalent to current practice, and makes our lives easier (bonus!).    Our pediatric colleague Patty, who managed to sit through 2 journal clubs on this topic in one day, voiced similar conclusions from the Department of Pediatrics discussion.

There’s always a caveat…

There is a potential concern for the induction of metabolic acidosis when administering IVF with equal chloride and sodium ion concentrations.   As Harwood pointed out, none of the three studies evaluated chloride or pH.   LR contains less chloride than NS, but is still hypotonic.  Future studies.

Antibiotics and COPD

Clinical Scenario and PICO question

Buds Ambulance brings a 68 yo male into room 4A with a chief complaint of 3 days of gradually progressive shortness of breath, now so bad that he had to quit smoking. His cough has gotten worse with more sputum, which he says is green and yellow.  He has wheezing and chest tightness at home, typical for his usual COPD exacerbation.  He doesn’t know if he had a fever, but he has had some chills. 

ROS: negative for CP, abdominal pain, N/V, leg pain or leg swelling, documented fevers.  

PMH:  HTN, COPD

Meds: Lotrel (amlodipine/benazapril),  Combivent MDI (albuterol/ipratropium), Flovent MDI (fluticasone)

Social Hx:  stopped smoking 2 days ago

PE:  142/82, 90, 26, 37.8, O2 Sat RA 90%

Dyspneic, speaking in short sentences.

HEENT:  neg

Lungs:  decreased breath sounds with inspiratory and expiratory wheezing bilaterally.

Cor:  RRR, no M/R/G

Abdomen: soft, NT, no mass or HSM

Extrem:  no C/C/E, nontender, no cords, has normal pulses bilaterally

ECG:  NSR, diffuse flattened T waves, no acute ST changes

CXR:  no infiltrate or CHF, has flattened diaphragms

Labs:  Normal BMP and negative troponin, WBC 10 K, Hgb 13, Platelets 300 K.

After Albuterol 10 mg/Ipratropium 0.5 mg, prednisone 60 mg po, and BIPAP, your patient is appearing more comfortable.  You are ready to call the next-up for admission and move on to the patient with non-specific CP in room 5, when your attending asks you about antibiotics.  There is no pneumonia on CXR, but the patient does appear to have some infectious symptoms…

PICO

P:  Moderate to severe COPD exacerbation, CXR without infiltrate but increased, purulent sputum

I:  Antibiotics + Usual care 

C:  Usual care

O:  Treatment Failure, Mortality, Antibiotic complications (allergic reaction, diarrhea)

The idea for this JC sprung out of the perceived clinical variability in our department in the treatment of COPD exacerbations with antibiotics.  As background, the 2004 ATS guidelines state that antibiotics may be initiated for outpatient or inpatient COPD exacerbations in patients with a change in their sputum characteristics (purulence and/or volume) and should be given if the patient is admitted to the ICU.  The 2010 GOLD (Global Initiative for Chronic Obstructive Lung Disease-joint project of NHLBI and WHO) guidelines recommend antibiotics for COPD exacerbations in patients with increased sputum purulence + increased sputum volume + increased dyspnea, or increased sputum purulence + increased volume or dyspnea, or intubated patients.

What is the evidence behind these expert recommendations?  As discussed below, it’s pretty modest.  Article #1 is the only recent RCT on the topic, Article #2 is a large retrospective cohort study evaluating outcomes in patients treated early with antibiotics, and Article #3 is a Cochrane review of all RCTs on the subject through 2005.

A historical word:  the background article by Anthonisen is still frequently referenced.  This study derived the most widely cited scale for grading the severity of acute COPD exacerbations, and combines pertinent symptoms into three categories:

Type 1 exacerbation:  All of the following symptoms are present: increased dyspnea, sputum volume, and sputum purulence.

Type 2 exacerbation:  Two Type 1 symptoms are present.

Type 3 exacerbation:  At least one Type 1 symptom is present plus upper respiratory tract infection symptoms or fever or increased wheeze or cough or increased resp. rate or heart rate.

In Anthonisen’s study, patients with Type 1 or Type 2 exacerbations had higher rates of clinical success and fewer episodes of deterioration.  Ok, it’s 24 years old, and a lot has changed in COPD management since then (BIPAP anyone?), but it’s good to be familiar with where it all started.

#1.  Daniels JMA, Snijders D, de Graaff CS et al.  Antibiotics in Addition to Systemic Corticosteroids for Acute Exacerbations of COPD. Am J Respir Crit Care Med 2010;181:150-157.

This RCT from the Netherlands compared outcomes in 265 COPD exacerbations (defined as increased dyspnea + increased sputum volume or purulence) treated with either doxy + steroids or placebo + steroids in hospital.   Patients with pneumonia were excluded.  The primary outcome measure was clinical response on Day 30.  Secondary outcomes included clinical success on Day 10, clinical cure on Days 10 and 30, lung function, CRP, symptoms, microbiological response and antibiotic treatment for lack of efficacy.  There was no difference in the primary outcome (61% clinical success in doxy group at Day 30, 53% in placebo group).  The authors stressed the positive results of the secondary outcome, clinical success at Day 10 (80% doxy, 69% placebo).  Clinical cure at Day 10 also was significantly higher in the doxy group.  Lung function results did not differ between the 2 groups, and symptom scores on a non-validated scale favored the doxy group at Day 10 but not at Day 30.  Bacteriological response was higher in the doxy group, but the clinical importance of this result is unknown, as colonization versus infection is difficult to determine, and persistent colonization even after appropriate antibiotic treatment is well described.  Serious adverse events occurred in 11 patients (9%) of the doxy group, including 7 deaths, as compared to 7 patients (5%) and 3 deaths in the placebo group.

Issues/Discussion:  As Christine brought up, Day 30 outcome is a strange choice.  We expect improvement earlier, and as Erin discussed, 10 day improvement can be very important with regards to improved quality of life, and also to help break the cycle of recurrent exacerbations.  Michelle mentioned the large number of exclusion criteria, limiting the external validity of the study (can we apply the results to our patients?).  Erik pointed out that the authors left out the number of eligible patients sampled (top of the fishbone diagram).  This is a recurrent theme, and increases the likelihood of a Type I (false positive) error, and therefore limits the internal validity of the study.  Erik also brought up the doubled mortality rate in the doxy group, which is not discussed further in the paper.

#2.  Rothberg MB, Pekow PS, Lahti M, et al.  Antibiotic Therapy and Treatment Failure in Patients Hospitalized for Acute Exacerbations of COPD. JAMA 2010;303:2035-2042.

This retrospective cohort study compared outcomes of hospitalized patients with COPD exacerbations but without pneumonia who either received antibiotics during the first two days of hospitalization or received late or no antibiotics.  The primary outcome was a composite measure of treatment failure that included mechanical ventilation, mortality, or readmission for COPD within 30 days.  Secondary outcomes included hospital cost and LOS and antibiotic associated adverse reactions.  Over the study period, 84,621 admissions from 413 acute care centers were included.  The risk of treatment failure was lower in the antibiotic treated patients (odds ratio 0.87; 95% CI, 0.82-0.92).  Each component of the composite primary endpoint was statistically lower in the group treated with antibiotics.  Patients treated with antibiotics had a higher rate of readmission for Clostridium difficile than those not treated with antibiotics (0.19%; 95% CI, 0.187%-0.193% versus 0.09%; 95% CI, 0.086%-0.094%).  

Issues/Discussion:  With retrospective studies it’s impossible to determine why certain patients did/did not receive treatment (antibiotics).  Although the authors attempted to correct for this using multivariable adjustments, the study remains vulnerable to selection bias.  As Matt discussed, the very large sample size allows the authors to look at rare outcomes (e.g. mortality) but with very large numbers, p values may be “significant” without there also being clinical significance (statistical versus clinical significance).   The readmission rate for C. difficile was low in both groups, but as Ben pointed out, the increasing rates of quinolone use lead to more C. difficile in the future.  Also, the patients treated with antibiotics were healthier overall, and this favors the antibiotic group.  Ben also calculated some numbers needed to treat.  Remember, the NNT = 1/ARR, and for the composite outcome, the NNT is 50.  For each of the components, the NTT is >100, so although the outcomes favor antibiotics, the treatment effect is modest.  Finally, Chintan made the important point that the study design will miss many patients with complications.  To be enrolled, patients needed a principal diagnosis of COPD or respiratory failure with COPD.  If a patient then had an MI, MI would likely be the principal ICD-9 code, and the patient would have fallen out of this study.

#3.  Ram FSF, Rodriguez-Roisin R, Granados-Navarrete A et al.  Antibiotics for exacerbations of COPD.  Cochrane Database of Systematic Reviews 2006, Issue 2. Art No.:  CD004403.

This Cochrane review includes all RCTs comparing antibiotics to placebo in patients with acute COPD exacerbations since 2005.  Eleven trials with 917 patients were included.  Their conclusion:  in COPD exacerbations with increased cough and sputum purulence, antibiotics significantly reduce the risk of short-term mortality (NNT 8; 95% CI 6-17) and treatment failure (NNT 3; 95% CI 3-5) with an increase in the risk of diarrhea (NNH 20; 95% CI 10-100) compared to placebo.  The authors admit that the results should be interpreted with caution due to differences in patient selection, antibiotic choice, the small number of trials, and the lack of controls for other interventions (steroids, BIPAP).  They acknowledge the growing resistance rates to common antibiotics and recommend limiting antibiotics to patients with COPD exacerbations and infectious symptoms who are moderately or severely ill.

Issues/Discussion:  As Jess discussed, there are huge variations in the definitions of COPD, the patient populations included, and there is no standard definition of “usual care”.  Gromis commented that the trials are in general old (only one published in the last 10 years), limiting the ability to generalize to current care of patients with COPD.  In addition, reviews like this suffer from publication bias:  studies demonstrating a positive treatment effect are more likely to be published than negative studies.

So, what’s our take home?  The data aren’t great, but modestly support antibiotics in patients with COPD exacerbations and infectious symptoms (in the absence of pneumonia).  Consensus of the faculty members in the room is to give antibiotics to patients with infectious symptoms.  Some give them to all COPD patients being admitted, and everyone agreed that antibiotics are indicated if the gestalt is that the patient looks “sick”.  The decision may be more difficult if the patient was just recently admitted or just recently finished a course of antibiotics.  Erik and Dan struck the cautionary note that given the doubled mortality in the first study for the antibiotic group, we may not be that far from clinical equipoise, and although they both prescribe a lot of antibiotics for these patients, we may also be doing harm (C. diff, etc).  As Dan pointed out, it’s ironic that in our last JC, we pushed hard against prescribing unnecessary antibiotics for AOM, and here we have a much more liberal prescribing policy.  Both conditions have reasonably high placebo success rates, but there are higher clinical consequences of treatment failure with COPD.  Final thought; if you’re giving antibiotics, think macrolides.  They appear to have anti-inflammatory effects at least partly independent of their anti-microbial effects, and are excellent agents against common respiratory pathogens.

Background Article

Antibiotic therapy in exacerbations of chronic obstructive pulmonary diseas. Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Ann Intern Med. 1987 Feb;106(2):196-204.

C.Diff treatment

Clinical Scenario and PICO question

You see a familiar name on the Picis tracking board- a 67 year old man you obs-admitted for pyelonephritis and mild dehydration 2 weeks ago. Today he presents with fever, abdominal pain, and diarrhea. These symptoms started 3 days ago and have become progressively worse.

PE: 118         116/64          20      38.8    98% on RA

Gen: awake and alert, appears uncomfortable

HEENT: tacky mucous membranes

Lungs: CTA Bilat

CV: tachycardia, no m/r/g, regular

Abd: mild diffuse tenderness, hypoactive BS, no masses, rebound

Rectal: watery, heme neg stool

 Labs:

WBC 26,000                      Na 146         

Hgb 11                             K 4    

Hct 33                              Cl 111

Plt 180                              HCO3 18

Neut 88%                         BUN  40

Cr  2.2

Glc  220

 You order oral metronidazole, IVF, a c.diff toxin assay, and arrange for re-admission (with C.diff isolation- thank you bed board). While waiting for a bed, your patient’s blood pressure decreases to 90/48. Because you have been nagged repeatedly by the PROCESS team, you add a lactate which comes back at 5.6.

 Besides excellent supportive care, are there alternative treatment options for your patient?

 P:  Ill patient with suspected C. diff infection and clinical deterioration

I:   Vancomycin, IV metronidazole, colectomy, fecal transplant

C:  Oral metronidazole

O:  Resolution of infection, ICU admission, death

Synopsis

Avoiding a Code 44 during your next Code Brown:  Updates in the Treatment of Clostridium difficile Colitis 

Thanks to Ted and Lisa Toerne for hosting a fabulous evening with Smoque BBQ and a lively discussion led by resident presenters Chris Yenter, Drew Dean, Abbi Balger, Shannon Lovett, Vijay Menon and Danielle Riccardi. 

By means of background, in 2010 the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Disease Society of America (IDSA) published updated clinical practice guidelines forClostridium difficile infection (Infect Control Hosp Epidemiol 2010;31:431-455).  The epidemiology of C. difficile has changed:  it is no longer a nosocomial infection restricted to hospitalized patients and nursing home residents.  Instead, it is also being identified in healthy adults and children in the community, sometimes without any recent antecedent antibiotic use.  There is also a new C. difficilestrain associated with fluoroquinolone use and commonly identified as NAP1/BI/027, which causes outbreaks of unusually severe and recurrent disease (ring a MRSA bell, anyone?).

Attempts have been made to identify optimal treatment strategies in this new age of killer C. difficile.  The three articles reviewed during JC are all referenced in the 2010 SHEA/IDSA guidelines.  None of the articles are of extremely high quality, yet they all helped shape national recommendations on the treatment of Clostridium difficile infection.  An EBM take-home point for the night is that clinical guidelines are not always based on high quality data, and parts of the guidelines may be derived solely from consensus opinion.  In the manuscript, guidelines should always identify both the strength of specific recommendations and the quality of supporting evidence. 

1.  Zar FA, Bakkanagari SR et al.  A Comparison of Vancomycin and Metronidazole for the Treatment of Clostridium difficile Associated Diarrhea, Stratified by Disease Severity.  Clin Infect Dis 2007;45:302-7.

This prospective double-blind RCT compared treatment with oral vancomycin (125 mg qid) versus metronidazole (250 mg qid) for 10 days in 150 patients with Clostridium difficile associated diarrhea (CDAD).  Overall cure rates were 84% in the metronidazole group and 97% in the vancomycin group (p= .006).  In patients with mild CDAD clinical cure rates between the groups were not statistically different (90% metronidazole, 98% vancomycin, p= .36).  However, in patients with severe CDAD, clinical cure with metronidazole was significantly less than cure with vancomycin (76% versus 97%, p= .02).  Recurrence rates were similar in the 2 groups.  Their conclusion was that although vanco and metronidazole are equally effective for the treatment of mild CDAD, vancomycin is superior in cases of severe CDAD.

Problems with this study:  the authors developed their own non-validated severity score to rank patients as having mild or severe CDAD (high age, high fever, high WBC, low albumin, ICU, pseudomembranous colitis).  Yenter mentioned that they didn’t look at IV metronidazole, limiting the ability to compare the 2 drugs.   Drew Dean highlighted the difference between an intention to treat  (ITT) analysis (preferred) and a per-protocol analysis.  This study performed a per-protocol analysis, and tossed out patients who withdrew or died during the study.  By not including those patients in the analysis of the results, there is a potential to derive misleading and inaccurate conclusions.  An example from Wikipedia: if people who have a more refractory or serious problem tend to drop out of a study at a higher rate, even a completely ineffective treatment may appear to be provide benefit if one compares outcomes before and after the treatment for only those who finish the treatment.  For the purposes of ITT analysis, everyone who begins the treatment is considered to be part of the trial, whether they finish the treatment/trial or not. 

Even given the significant methodologic problems of this study, Erik pointed out that the large effect size supports the validity of the results.

2.  Lamontagne F, Labbe E et al.   Impact of Emergency Colectomy on Survival of Patients with Fulminant Clostridium difficile Colitis during an Epidemic Caused by a Hypervirulent Strain.  Ann Surg 2007;245:267-272.

These authors sought to determine if emergency colectomy for fulminant CDAD provides a mortality benefit.  In this retrospective observational cohort study, 161 patients with 165 cases of CDAD requiring ICU admission or prolonged ICU stay for severe CDAD were included, and the primary outcome was mortality within 30 days of ICU admission.  There was an overall 53% mortality rate, with almost half of the deaths occurring within 2 days of ICU admission.  Independent predictors of 30 day mortality were WBC >/= 50 K, lactate >/= 5, age >/= 75, immunosupression, and vasopressor dependent shock.  Adjusting for these confounders, colectomy reduced the odds of death by 78% (adjusted odds ration 0.22, 95% CI 0.07-0.67, p=0.008).  The authors attempted to use subgroup analysis to identify patients more likely to benefit from colectomy (age >/= 65, immunocompetent, WBC >/= 20, or lactate between 2.2 and 4.9), however as Sam pointed out, the subgroups are small, and subgroup analysis should only be used to generate future hypotheses.  Dan stressed the authors’ finding that without a colectomy, 94% of patients with a WBC >/= 50K or with lactate >/= 5 died within 30 days of admission to the ICU, or as Shannon said, “think about involving surgery earlier than when the patient is in the unit with a lactate of 12”.

As Shannon pointed out, no timeline was provided on when the colectomy was performed.  In addition, the decision to operate was based on individual surgeon preference.  As Abbi mentioned, this study was performed during an epidemic caused by a hypervirulent strain, and limited to 2 hospitals in Quebec, which limits its external validity.  Ted brought up the question of whether or not patients are receiving EGDT/optimal medical care, which would influence outcomes. 

Although there are significant limitations to this study, the results are similar to the only other colectomy study referenced in the SHEA/IDSA guidelines.

3.  Aas J, Gessert CE, et al.  Recurrent Clostridium difficile Colitis:  Case Series Involving 18 Patients Treated with Donor Stool Administered via a Nasogastric Tube.  Clin Infect Dis 2003;36:580-5.

This case series examined the results of treating recurrent CDAD with a stool transplant.  Relapse rates after treated CDAD are around 20%, and may be higher with new more virulent strains.  Relapse begets relapse, and patients end up receiving multiple courses of antibiotics.  Administering donor stool, either by NG or per rectum, has been attempted to restore the normal healthy colonic bacterial flora.  In this single institution study, of 18 patients with documented recurrent CDAD, 2 patients died of unrelated illnesses, 1 patient had an isolated recurrence of CDAD, but the other 15 had no relapses at 90 day follow-up.  The protocol to prepare the stool (usually donated from healthy family members or less commonly from healthy donors) is outlined.  All you need is a household blender and a paper coffee filter…really.  Donors were screened for blood born and enteric pathogens.  The authors stress that the patients were uniformly receptive to the idea of stool transplantation, likely reflecting the significant disability and frustration associated with recurrent CDAD infection.  This is limited case series data from a single institution, but the idea of restoring bacterial homeostasis is appealing, or per Ted Toerne, “Bring on the filtered stool”!

Three Bottom lines: 

#1:  Article 1 is referenced in the 2010 CDAD clinical guidelines from SHEA/IDSA, and their treatment recommendations are provided in the table below.  Importantly, elevated WBC or creatinine, and shock or ileus/megacolon should prompt more aggressive therapy, either with vancomycin or with vanco + IV metronidazole.

#2:  Consider involving surgery early in cases where pressors are needed, or if toxic megacolon, perforation, high WBC, or lack of response to medical therapy (Harwood).

#3:….and although we’ll never order a stool transplant in the ED, Ben Harris is ready to donate if needed.

 


 
Background articles
1) Clostridium difficile--more difficult than ever. Kelly CP, LaMont JT. N Engl J Med. 2008 Oct 30;359(18):1932-40. Review. No abstract available. Erratum in: N Engl J Med. 2010 Oct 14;363(16):1585.
 
2)  Patterns of antibiotic use and risk of hospital admission because of Clostridium difficile infection.  Dial S, Kezouh A, Dascal A, Barkun A, Suissa S. CMAJ. 2008 Oct 7;179(8):767-72.

Treatment of Otitis Media

Clinical Scenario and PICO question

It’s 3 am, and you’re working another fabulous moonlighting shift in the PED.  Little Johnny is brought in by his mother because of concern that he has an ear infection.  His mother relates that he has had a fever of 101, responsive to Ibuprofen, but that he has cold sx, and is crying and pulling at his right ear.   All symptoms for one day.

ROS:  negative for N/V/D, no SOB, +URI sx.  Still drinking, normal diapers, no rash, no exposures.

PMH  Term, SVD, no recent illness/antibiotics, no medications or allergies, Immunizations are UTD.

Exam:  Well appearing 24 month old male, T 38.2, RR 20, HR 100, BP 90/55.  Wt. 12 Kg.

HEENT:  Profuse rhinorrhea, OP no erythema/exudate.  Moist mucous membranes.

Left TM normal, Right TM erythematous, bulging, mild pain with exam.  No perforation/otorrhea.

Neck supple, NT, no meningismus, has mild anterior cervical adenopathy bilat.

Lungs CTA, Cor RRR, Abdomen soft and NT, no mass/HSM.  Extrem normal cap refill bilat.

Skin no rashes.  

Is playful, trying to ingest your stethoscope.

 You are about to print out a script for a gallon of Amoxicillin and wish the mother good luck with the diarrhea, when your attending says “Wait a minute.  Are you familiar with the 2004 AAFP/AAP guidelines on acute otitis media?  Does Little Johnny really need antibiotics tonight?”   You think to yourself that Kulstad (either) must be losing it…of course AOM needs antibiotics.  And how could you talk a mother into deferring antibiotics?  What is this crazy talk?  Still, you do have a few minutes to look into it…

 PICO

P:  Healthy infant >6 months of age meeting the AAP/AAFP diagnosis of AOM

I:   Deferring antibiotics for 48 hours after the ED visit

C:  Immediate prescription for antibiotic treatment

O:  Duration of sx (time to clinical cure), % prescriptions filled, development of complications such as mastoiditis, parental satisfaction, adverse medication effects (diarrhea, rash).

Synopsis

Thanks to Scott and Cindy Altman for hosting, and to Christian DenOuden, Michelle, Dave Cummins, Anna, Gromis and Brad for presenting.

Background:  An estimated 15 million antibiotic prescriptions are written annually for the treatment of pediatric acute otitis media (AOM) in the United States.  While the vast majority of children in the US receive antibiotics for AOM, prescribing practices differ in Europe; 60% of kids in the UK and only about 30% of kids in the Netherlands are treated with antibiotics.  Approximately 80% of children with AOM recover within 3 days without antibiotics.  Antibiotic cost, diarrhea/rashes, allergy and growing antibiotic resistance must be weighed against the potential benefits of increased cure rate, shorter symptom duration, and decrease in complications including deafness, meningitis, and mastoiditis.  In 2004, joint practice guidelines for the diagnosis and management of AOM were issued by the American Academies of Pediatrics and Family Practice.   Besides requiring the presence of 1) acute symptoms and signs, 2) evidence of effusion and 3) evidence of inflammation to make the diagnosis, and a recommendation for treatment with high-dose amoxicillin as the first line antibiotic, these guidelines included a option for 48-72 hour observation without antibiotics for a subset of children.  In this journal club, we discussed articles examining a wait-and-see approach to the treatment of AOM, non-treatment with antibiotics, and the effect of antibiotics on rates of mastoiditis.

Article #1:  Spiro DM, Tay KY, Arnold DH, et al.  Wait-and-See Prescription for the Treatment of Acute Otitis Media.  JAMA. 2006;296:1235-1241.

In this RCT, 283 children between the ages of 6 months and 12 years seen in the ED with a clinical diagnosis of AOM were randomized to either receive a wait-and-see prescription (WASP) for antibiotics to be filled in 2 days if the child was not improving or was worsening, or a standard prescription (SP) to be filled and started directly after the ED visit.  All participants received complimentary bottles of ibuprofen and otic analgesic drops.  Exclusion criteria included recent antibiotics, clinical toxicity, immunocompromise, myringotomy tubes/perforated TM, additional bacterial infection, hospitalization and uncertain access to medical care.  The primary outcome was the proportion in each group that filled the antibiotic prescription.  Secondary outcomes included clinical course of illness, adverse effects of meds, school/work missed, and unscheduled medical visits.  Standardized phone follow-up occurred several times from 4 to 40 days after enrollment (>90% completed at least one follow-up call).  Of 776 patients assessed for eligibility, 308 were not enrolled because they did not meet inclusion criteria (27% had been treated with antibiotics in the prior week).  Antibiotic prescriptions were not filled for 62% of WASP patients and 13% of SP patients.  No serious adverse effects were reported in either group.  Of parents reporting otalgia, there were statistically significant but minor differences between the WASP and SP groups in total days of otalgia (2.4 vs. 2.0 respectively, P=.02).  There was statistically significant more diarrhea in the SP group (8% vs. 23%, P<.001).  There were no significant differences in duration of fever or unscheduled medical visits.  The authors conclude that the use of WASP reduced the use of antibiotics by 56% and is a successful strategy for the ED.  This study may not be generalizable as it was limited to one urban ED, and there were a number of exclusion criteria (although many kids would qualify).  In addition, the half-day of decreased otalgia seen in the SP group might be magnified in situations where parents are not receiving complimentary analgesics.  On the other hand, there was a significant increase in diarrhea in the SP group, and no difference between the groups in the rate of unscheduled medical visits (a potential surrogate for treatment failure).  This study differs from the AAFP/AAP guidelines in that it includes younger children and does not distinguish between mild vs severe AOM when making decisions about WASP vs SP. 

Bottom line:  The wait-and-see prescription strategy works in the ED, decreasing filled antibiotic prescriptions by 50%.  Additional positive outcome is a significant decrease in diarrhea, but the study found an overall increased duration of otalgia by a half day in the WASP group.

Article #2:  Le Saux N, Gaboury I, Baird M, et al.  A randomized, double-blind, placebo-controlled noninferiority trial of amoxicillin for clinically diagnosed acute otitis media in children 6 months to 5 years of age.  CMAJ. 2005;172:335-41.

These authors took a bolder approach, randomizing 531 children  between the ages of 6 months and 6 years with a clinical diagnosis of AOM to either amoxicillin 60 mg/kg/day or placebo for 10 days.  Exclusion criteria included recent antibiotics, immunosuppression, comorbid or chronic disease, ear surgery, otorrhea, or recurrent AOM.  The study was conducted at three Canadian sites, including one ED.  Again all participants received complimentary analgesics.  Parents were contacted at 1, 2, 3 days after randomization and again between 10 and 14 days.  If at any of the initial three interviews the child was not improving or was worsening, a medical re-assessment was advised.  Additional follow-up and tympanometry to assess effusion were performed at 1 and 3 months.  The primary outcome was clinical resolution defined as no new antibiotics (other than initial amoxicillin in treatment group).  Secondary outcomes included fever and activity level on days 1, 2, 3 as well as rash and diarrhea in the first 2 weeks.  Of 1924 children screened, 963 were eligible, 531 proceeded to randomization, and 512 were included in the data analysis.  As Dave Cummins noted, a large number of eligible children were not randomized, either because the doctor wanted to treat (were these children different? sicker?) or because parents refused consent (what kinds of parents/kids were in this group?).  In the per-protocol analysis, clinical resolution rates at 14 days were 84.2% for the placebo group and 92.8% for the amoxicillin group (absolute difference of 8.6%).   Results were similar in the intention-to-treat analysis.  Interestingly, there was a smaller difference (6%) in resolution rates between the 2 groups in children <2 years old (more viral AOM?  more non-specific fever without a source labeled AOM?).  NNT to prevent one treatment failure within 14 days was 11.0 (95% CI 6.83-30.0).  Overall, more children in the placebo group had fever and pain in the first 2 days (approximately 10% more children with fever/pain in placebo group during first 2 days).  There were no significant differences in activity level, occurrence of rash or diarrhea, recurrent AOM, or middle ear effusions by tympanometry in the 2 groups.  Even with free analgesics, the average number of daily analgesic doses administered by parents in each  group was 2.  I wondered how many children were sent for medical reassessment on Day 1 because they weren’t improving.  If a child showed up in the office/ED for reassessment, you could imagine a significant likelihood that the child would leave the reassessment visit with an antibiotic prescription.  If those kids instead had been given 2 days before the first follow-up interview and possible trip back to the doctor, I wonder if more of them would have been improving on their own anyway, not been recommended to have a re-assessment, and the resultant differences between the groups may have been smaller.  Just guessing, of course.

Finally, to throw in a bit of statistics:  the significance level of a hypothesis test is the probability of wrongly rejecting the null hypothesis, if it is in fact true (false positive).  It is the probability of a type I error and is set by the investigator in relation to the consequences of such an error. That is, we want to make the significance level as small as possible in order to prevent, as far as possible, the investigator from inadvertently making false claims.  Usually, the significance level is chosen to be 0.05 (or equivalently, 5%).  As Erik pointed out, in this study, the authors chose a type I error of 10%, giving them a significant (10%) risk of the results of the study being falsely positive.

Bottom line:  Although the majority (>80%) of placebo patients were better at 14 days, the NNT to prevent one treatment failure by giving antibiotics was 11.0.  Overall, approximately 10% more children in the placebo group than in the antibiotic group had fever and pain in the first 2 days.  There were no significant differences in activity level, occurrence of rash or diarrhea, recurrent AOM, or effusions at follow-up in the 2 groups.

Article #3:  Thompson PL, Gilbert RE, Long PF, et al.  Effect of Antibiotics for Otitis Media on Mastoiditis in Children:  A Retrospective Cohort Study Using the United Kingdom General Practice Research Database.  Pediatrics. 2009;123:424-430.

Finally, RCTs will never be powered to identify differences in the rates of  rare but potentially devastating complications of AOM.  This third study examined whether the rates of mastoiditis have increased in the UK in association with the decline in antibiotics prescribed to children for AOM.  The authors conducted a retrospective cohort study using the UK General Practice Research Database, representative of practices in the total UK and comprising 6% of children in the UK census population. Children between the ages of 3 months and 15 years with a diagnosis of mastoiditis were identified (n=854), of whom only one third had a diagnosis of AOM in the antecedent 3 months .  Although the risk of mastoiditis after AOM was 1.8 per 10,000 episodes after antibiotics compared with 3.8 per 10,000 episodes without antibiotics, 4831 cases of AOM would need to be treated with antibiotics to prevent 1 child from developing mastoiditis.   The incidence of mastoiditis remained stable between 1990 and 2006, although the incidence of AOM diagnoses fell by 34% during this time and antibiotic prescribing for AOM declined by 50%.  Interestingly, while the incidence of mastoiditis was highest in infants, lowest in 2-year-olds, and increased steadily with age thereafter, the incidence of AOM steadily decreases with increasing age (epidemiology doesn’t match up between the 2 diseases).

Bottom line:  While it’s a potentially very serious condition, mastoiditis is rare, and only about a third of patients diagnosed with mastoiditis are treated in the prior 3 months for AOM.  While antibiotics decrease the risk of developing mastoiditis, nearly 5,000 children with AOM would need to be treated with antibiotics to prevent one case of mastoiditis (NNT= 5,000…not a sound prevention strategy).  Recognizing clinical signs of mastoiditis, especially in older children, is key to early diagnosis and successful treatment.

Wrap-up:  Although the majority of folks in the room were willing to try the wait-and-see prescription approach for AOM, a few still prefer to treat all AOM with antibiotics, citing the modest increase in clinical cure rate and small but real decrease in duration of pain.  This must be weighed against the long-term effects of antibiotic resistance and increased risk of diarrhea (not inconsequential in this age of community associated Clostridium difficile), as well as cost.  It’s an excellent opportunity to involve parents in the decision making process.  All in the room agreed that free bottles of ibuprofen and otic analgesic drops for parents to take home at 3 am would be extremely helpful both with patient satisfication and to get buy-in for the wait-and-see approach.  Write for generic oticaine otic drops (benzocaine) now that Auralgan has added vinegar to its formulation and is no longer generic!

Diagnosis and Treatment algorithm

Bronchiolitis

Treatment of Bronchiolitis-at least for this year.

#1.  Plint AC et al.  Epinephrine and Dexamethasone in Children with Bronchiolitis.  NEJM 2009;360:2079-89.  

In this RCT, 800 infants 6 weeks to 12 months were randomly assigned to one of four study groups:  2 treatments of nebulized epinephrine + 6 doses oral dexamethasone, nebulized epi + oral placebo, nebulized placebo + oral dex, or nebulized placebo and oral placebo.  Primary outcome measure was hospital admission within 7 days of ED visit.  In the unadjusted analysis, only the kiddos in the nebulized epi + oral dex group had a lower risk of admission (NNT = 11).  When the results were adjusted for multiple comparisons, there was no statistically significant difference between groups.  No serious adverse effects in any group.

The statistical debate this brought out was between the traditional frequentist interpretation which relies on p values to define significance, and the increasingly popular Bayesian approach to analyzing study results which gives more importance to the effect size of the therapy and the risks of the therapy, rather than to a p value.  So, for some in the room, even thought the adjusted p value was not statistically significant, a NNT of 11 with relatively benign therapies would be worth it.  A cautionary note-this study required giving dex in the ED and then for 5 additional days.   There were also a fair number of exclusion criteria:  excluded prior wheezer/asthmatics, cardiopulm dz, severe distress, preemies, varicella exposure, immunodeficient.  Inclusion criteria required RDAI scores (bronchiolitis score) 4-15, indicating mild-fairly severe bronchiolitis.

        

#2.  Corneli HM et al.  A Multicenter, Randomized, Controlled Trial of Dexamethasone for Bronchiolitis.  NEJM 2007;357:331-9.  

In this large RCT, 600 infants (2 to 12 months) with moderate to severe bronchiolitis were randomized to receiving either one dose of dexamethasone (1 mg/kg) or placebo.  Primary outcome was hospital admission after 4 hours of ED observation.  Although both groups had improvement during their ED course, there was no significant difference in 4 hour admission rate (NNT = 300), and no significant difference in bronchiolitis scores or other later outcomes including hospital LOS, or later medical visits/admissions.  Again, no significant adverse events.   Although the authors chose an ED relevant outcome (admission rate), there was some discussion that steroids might not make much of a difference in the first few hours.  Then again, there were no differences in their secondary outcomes either.  As in the first study, similar inclusion/exclusion criteria; as in first study, they excluded prior wheezers or asthma history.  And, although infants with known asthma were excluded, they did look at subgroups of pts with eczema or FH of asthma as markers for higher risk of asthma/potential benefit for steroids, also looked at different age groups, but in all subgroups steroids still no benefit.  In both of these studies, the average RDAI score of 8-9 puts these patients in the moderate severity category, and upper limit of age in both studies was 12 months;  would older (maybe asthmatic), or less sick/more sick kids behave differently?

Is there any harm from steroids?  Unknown for single use, but I wonder if giving steroids sets the pt up to receive steroids more easily if they come in again with wheezing associated with a URI.  In a NEJM article by Ducharme in 1/22/2009,  preschool children receiving recurrent inhaled steroids at the beginning of URIs had less rescue oral steroid use, but also had smaller gains in height and weight.  Another study  (700 kids) in that same issue of NEJM (Panickar) found no benefit from oral steroid use in preschool children with viral-induced wheezing .

#3.  Walsh P et al.  Comparison of Nebulized Epinephrine to Albuterol in Bronchiolitis.  AEM 2008;15:305–313.

This study deserves 2 initial strong shout-outs; Kate McQuillan, formerly research director in our department is an author, and ACMC was the second study site.  Other studies have shown short-term clinical improvement with albuterol, but no sig. decrease in admission rates.  This RCT compared 703 patients up to 18 months old receiving either 3 doses of nebulized racemic albuterol or one dose of nebulized racemic epinephrine + 2 saline nebs.   Primary outcome was successful ED discharge (no admission for subsequent 72 hours).  Admission decision was made after 2 hours in the ED.   Unlike the other 2 studies, the inclusion criteria were broad, and they included former preemies and prior wheezers (and had a higher upper age limit than the other 2 studies).  The crude analysis showed no difference in the 2 groups, but when they adjusted for severity of illness, infants receiving albuterol were slightly more likely to be successfully discharged (NNT = 6 for mild, NNT = 11 for moderate, NNT = 40 for severe).   These results held up for subgroups of first wheezers and patients less than 12 months of age.  A hx of recurrent wheezing or FH of asthma also did not change the treatment effects.  A few issues; their illness severity score was created by the authors, and was meant to be a research tool, not a clinical instrument-impossible to decipher.  Admission decisions were made after only 2 hours after receiving study drugs, and pts with a prolonged ED stay were called admissions.  The epi group had more moderately ill (and fewer mildly ill) patients than the albuterol group→potential bias in favor of epi.  The study design gave 3 active treatments of albuterol then admission decision which may favor the albuterol group (epi group received saline during last 2 treatments).  Few adverse effects, but one death in the epi group was reported within 30 days (what if the trial had been larger?).  Number of eligible but not enrolled patients unknown.

So, where does that leave us?  Easy first choice-suctioning, and then more suctioning.  Some kind of nebulization treatment, even if it’s just a saline neb, is very reasonable.  Trying an albuterol or epinephrine neb should be generally safe, and a small-moderate percentage of infants will respond to albuterol or epi.    From a show of hands at the end of the JC, the majority in the room were willing to try nebulized epinephrine and dexamethasone.   Need to remember, if you’re going to give epi and dex based on the Plint article, it’s 6 days of steroids.  Others in the room were not convinced of the synergy of inhaled epinephrine and dexamethasone, and based on the negative Corneli steroid article, would not give steroids.  Harwood said it best-during the past 30 years, treatment for bronchiolitis has been cyclical-new studies come out, therapies change, we change our practice, then newer studies refute the prior findings.  

While it would be satisfying to have a clear consensus, a variety of treatment options can be supported by the current literature, and there is no single clear correct answer.  The quest will continue-we briefly touched on nebulized hypertonic saline, but there had only been 4 published studies with a total of 254 infants as of a Cochrane review in 2009, and although HS may significantly reduce hospital LOS and clinical severity scores, it has been primarily studied in inpatient populations, in small studies, and in many cases the patients also received bronchodilators (not ready for ED prime-time).

tPA and CVA

The treatment of acute ischemic CVA with TPA from 3 to 4.5 hours after symptom onset

1)  Tissue plasminogen activator for acute ischemic stroke.  The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.  NEJM. 1995;333:1581-7.

NINDS is a RCT trial in two parts evaluating the use of TPA in ischemic CVA when given within 3 hours of symptom onset.  Part 1 (291 patients) evaluated clinical activity, or whether there was  significant neurologic improvement at 24 hours.  Results of Part 1 were negative (no difference at 24 hours between TPA and placebo).  Part 2 evaluated clinical outcome at 3 months, using patients from Part 1 and an additional 333 patients.   Part 2 demonstrated significant results:  as compared with placebo, patients treated with TPA were at least 30% more likely to have minimal or no disability at 90 days on clinical assessment scales (absolute increase in favorable outcome 11%, NNT 9).  This is balanced against a 10X increased risk of symptomatic intracranial hemorrhage (6.4% in TPA group, 0.6% in placebo group).   A couple of common criticisms of NINDS:  first, the trial selectively enrolled an equal number of patients treated within 0-90 and 91-180 minutes of stroke onset, with greater benefit shown for those in the former group.  In general practice, you wouldn’t see as many patients qualify for early treatment, making the results less generalizable.  Second, stroke severity in the group treated from 90-180 minutes was greater in the placebo than in the tPA group, again potentially biasing the results in favor of treatment. 

The AHA gave TPA a Class I  recommendation for use in ischemic CVA in 2000.  Few studies have provoked the degree of rancorous debate and number of re-analyses as NINDS.  At JC we mentioned the graphical analysis of the NINDS data from one of TPA/CVA’s biggest opponents, Jerry Hoffman (with Dave Schriger, Annals of EM, Sept. 2009).  Their article is attached, and they promoted it as an attempt to bring transparency to the data, and to offer individual patient analysis rather than conclusions about groups of patients.   In the spirit of being fair and balanced, I have also attached a pooled analysis of ATLANTIS, ECASS, and NINDS by Hacke et al published in Lancet in 2004 (thanks Ejaaz).  Although ATLANTIS, ECASS I and ECASS II enrolled most patients after 3 hours, in studies evaluating patients  in these trials enrolled in under 3 hours, there were trends towards benefit in those treated with TPA (references available on request).

Although ACEP and CAEM both recommend the use of TPA in acute ischemic stroke up to 3 hours after symptom onset, they strongly reiterate the need to follow the strict inclusion/exclusion criteria from NINDS and to establish institutional safety guidelines (ACEP and CAEM), and to advocate for neuroradiologist and close neurology involvement (CAEM).  AAEM states that efficacy, safety and applicability evidence is insufficient to warrant the classification of TPA in CVA as standard of care.

Things became even more heated this year, when the AHA gave a Class I (Level B evidence) recommendation for the use of TPA in the setting of CVA from 3-4.5 hours after symptom onset.  This expansion of the time window was based on one study: ECASS III. 

2) Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.  NEJM. 2008;359:1317-29. 

ECASS III was a RCT of 821 patients, alteplase vs placebo, time to treatment 3-4.5 hours after symptom onset with a median time for administration of 4 hours.  Primary outcome:  disability at 3 months (dichotomized modified Rankin scale-favorable or unfavorable), with a secondary efficacy end point of a 90 day global outcome measure.   Mean NIHSS stroke scale 11.  With regards to the primary endpoint, there was a statistically significant increase in the number of patients with favorable outcome when comparing alteplase to placebo (52.4% vs. 45.2%, absolute increase in favorable outcome 7.4%, odds ratio 1.34, NNT 13.5).  The secondary outcome was also significantly improved with alteplase as compared with placebo.   There was no significant difference in mortality (7.7% alteplase, 8.4% placebo).  The incidence of symptomatic ICH was significantly increased (over 2X) in the alteplase group (7.9% vs. 3.5% by NINDS definition). 

Although the AHA based their recommendation uniquely on ECASS III, there are a number of other earlier published thrombolytic/CVA trials which attempted to push the time window and had negative results.  As one example, we reviewed ATLANTIS. 

3) Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset.   The ATLANTIS Study:  a randomized controlled trial.  JAMA. 1999;282:2019-26.

ATLANTIS was designed to run concurrently with NINDS, assessing efficacy and safety of TPA when administered from 0-6 hours after symptom onset in patients with ischemic CVA.   However, safety concerns resulted in stopping enrollment after 5 hours.  Then, when the results of NINDS were published, the trial protocol was again changed, with the treatment window changed to 3-5 hours after symptom onset.  ITT population 613 patients.  Primary outcome excellent neuro recovery at 90 days (NIHSS score less than/equal 1). No significant difference in patients treated with TPA vs. placebo on either primary outcome or on secondary functional outcome measures.  Symptomatic ICH 7.0% with TPA, 1.1% placebo (significant), but no significant difference in mortality.

Our clinical vignette patient would have met the inclusion/exclusion criteria for both ECASS III and ATLANTIS.   There will be continued controversy surrounding the use of TPA in acute ischemic stroke, whether the patient is ready for the drug 2 or 4 hours after symptom onset.  Many scientists have called for more studies, but given the cost involved with mounting these large multi-center trials, it’s unlikely to happen (definitely no interest on the part of Genentech!).   Within the group of physicians present at JC, there were also a variety of opinions on TPA’s merit.  Certainly one’s own personal opinions are likely to influence how you present the pros/cons of TPA to a patient and family. 

For all 3 of these studies, there are concerns about internal validity (how many patients were screened and not enrolled in these studies involving 100 + centers) and external validity (what happens when you move the treatment setting from a highly regulated stroke center to the general community-in Cleveland, 16% symptomatic ICH rate, and 3X the mortality in patients treated with TPA vs. placebo).

Other important points: the exclusion criteria for ECASS III are extensive!!  It’s imperative to be familiar with the ECASS III exclusion criteria, in order not to tip the narrow balance between benefit and risk.  A couple of examples:  all three trials used a BP of 185/100 as an exclusion criteria.  ATLANTIS and ECASS III specified that IV BP meds were not allowed.  Also, both ATLANTIS and ECASS III excluded patients >80 years old.  This excludes a large number of patients.  Patients with severe strokes were excluded in both ECASS III and ATLANTIS.  Although patients with more severe strokes have a greater risk of ICH, they also have great potential to be helped by TPA and avoid severe disability (see:  the NINDS t-PA Stroke Study Group. Stroke. 1997 Nov;28(11):2109-18  and the attached pooled analysis-thanks again Ejaaz).  This ties in to the broader philosophical question of personal risk.  We discussed that one approach with patients/families is to assess the degree to which a patient is a risk taker (“I’d rather  take a chance of bleeding into my brain than be a vegetable”) or risk averse (“the weakness isn’t too bad, and with aggressive rehab, is likely to improve”).   Considering the value system of your patient is the third pillar of Evidence Based Medicine (besides examining the evidence and using clinical experience).  Joan Coughlin also brought up the excellent point that although it’s not exciting, early aggressive rehab is extremely important in stroke care, and can help many patients achieve significant improvement (in ATLANTIS, with baseline NIHSS score of 11, 32% of placebo patients with excellent neuro recovery, and in ECASS III, 45%).

In the TPA/CVA packet in the ED, there are simple statistics about the risk/benefit of TPA when given within 3 hours.   This information may be helpful when speaking with patients/families, but you will now also need similar talking points for the extended time window.  It was recommended by several seasoned faculty to be familiar with both NINDS and ECASS III (and ideally, the other thrombolytic trials).  This will give you the best chance to share as accurate and balanced information as possible when advising patients and families about this complicated, high stakes therapeutic decision.



Steroids in Meningitis

Adjunctive Steroids in the Treatment of Adults with suspected Bacterial Meningitis

1) Dexamethasone in Adults with Bacterial Meningitis
De Gans, et al, NEJM Nov 14, 2002;347:1549-1556.

RCT, Europe, 301 patients, >16 yo, suspected bacterial meningitis, primary outcome Glasgow Outcome Scale at 8 weeks (death/disability), secondary outcomes death, focal neuro abnormalities, hearing loss, GI bleed, fungal infection, zoster, hyperglycemia.  Significant reduction in mortality and risk of unfavorable outcome using dexamethasone 10 mg IV q 6 hours for 4 days (mortality 7%) vs. placebo (mortality 15%), both groups received IV Amoxicillin or empiric antibiotics based on local resistance patterns (yes, Amox works well in Holland).  No beneficial effect seen in dex group with regards to neuro sequelae including hearing loss.  
Points of interest for comparison:  Confirmed meningitis (in this study defined by CSF culture pos = 78%, probable meningitis CSF culture neg = 22%).  Median duration of symptoms 24 hours.  Breakdown of bacterial etiologies when known:  S. pneumoniae 36%, N. meningitidis 32%, other bacteria  10%, including H. flu 1%.  In this study patients who had received prior antibiotics were excluded.  Low risk of adverse events/no sig. difference in rates of steroid associated adverse effects between groups. Interesting point made in article about neuro sequelae; although no benefit seen in steroid group, neuro sequelae seen predominantly in the most severely ill patients, and proportion of severely ill who survived to be tested was larger in dex group.  Also very interesting that positive steroid effects (death/disability) appear to be significant only in S. pneumoniae group (other bacterial etiologies NS).

2) Corticosteroids for Bacterial Meningitis in Adults in Sub-Saharan Africa
Scarborough et al, NEJM Dec 13, 2007;357:2441-2450.

RCT, Malawi, 465 patients, >16 yo, suspected bacterial meningitis, primary outcome mortality at 40 days, secondary outcomes time to death, combined death/disability at day 40, hearing impairment at day 40, death at 10 days, death at 6 months.  No difference in either primary or secondary outcomes (40 day mortality 56% dex, 53% placebo) using dexamethasone 16 mg IV bid for 4 days vs. placebo, both groups received 2 gm IV or IM ceftriaxone bid for 10 days (route independently being evaluated in study, no difference in mortality).
Points of interest for comparison:  Confirmed meningitis 70%, probable meningitis 22%.   Breakdown of bacterial etiologies when known:  S. pneumoniae 59% of total patients, N. meningitidis 4%, other gram neg 5% (including <1% H. flu), Crypto 4%, TB 1.5%.   Breakdown of HIV status available for 93% of total patients, and 90% were HIV +, median CD4 count 102.  Prior antibiotics 37%, including 20% having received prior parenteral antibiotics, but analysis of prior antibiotic + patients still with no steroid advantage.  Median length of illness 3 days (more than Europe, same as Vietnam).  Low risk of adverse events/no sig. difference in rates of steroid associated adverse effects between groups.   Huge mortality, in population with extremely high rate of advanced HIV disease, and therefore may already have an attenuated host response (steroids may not confer additional anti-inflammatory benefit).
  
3) Dexamethasone in Vietnamese Adolescents and Adults with Bacterial Meningitis
Mai et al, NEJM Dec  13, 2007;357:2431-2440.

RCT, Vietnam, 435 patients, >14 yo, suspected bacterial meningitis, primary outcome mortality at one month, secondary outcome death/disability at 6 months.  No difference in either outcome (one month mortality 10.1% dex, 12.4% placebo) using dexamethasone 0.4 mg/kg IV q 12 hours for 4 days vs. placebo, both groups received 2 gm IV ceftriaxone q 12 hours for 10-14 days.   There was a significant benefit from dex in reducing deafness overall and in subgroups.  For patients with confirmed meningitis (69%), both outcomes were significantly improved with dexamethasone, while for probable cases (28%),  dex was associated with an increased risk of death at one month.  Why?  Proposed explanation that some patients in “probable meningitis” group ended up diagnosed with TB meningitis but TB meds were delayed, and more of these patients received dex; TB with high mortality anyway, and will do worse if given dex and no TB drugs.  
Points of Interest for comparison:  Breakdown of etiologies of meningitis when known:  Streptococcus suis 27% of total patients, S. pneumoniae 13%, all others each <5% (Neisseria 4%, H. flu 2%).   S. suis common in Asia, and although less likely to kill you, is highly associated with deafness.  Also important when comparing studies:  low rate of HIV (<1%),  high rate of prior antibiotics (65%), and no mortality difference in dex/placebo groups who had received prior antibiotics.  Median duration of illness 3-4 days.  Low risk of adverse events/no sig. difference in rates of steroid associated adverse effects between groups.

Bottom line:
Vast majority at journal club would give the vignette patient (young adult, healthy, CSF with pus) steroids and then antibiotics.  Based on first study and decrease in mortality 15% → 7% with steroids, and lower risk of negative outcome.   Most vocal contrarian: Erik Kulstad, who pointed out that cognitive function may be negatively impacted by steroids, and therefore need to weigh mortality benefit vs. potential cognitive harm.  This brought out the importance of discussing potentially controversial treatment plans with family/patients; not only is patient preference the third pillar of EBM, but documenting these discussions of risk/benefit can also help protect you from a medico-legal standpoint (is it more important for your patient to survive, or to be a brainiac?).  Also important to remember that although no significant increase in GI bleeding, studies were relatively small-might see more negative outcomes with larger studies.   There was clear consensus in the room NOT to treat patients with meningitis and advanced HIV with steroids (Malawi study).  Also important to realize the heterogeneity of the studies and our patients-different bacteria, different chronic medical conditions/genetics of patients, different antibiotic choices (vanco/blood brain barrier), time to antibiotics-- all may factor into decision process.