Eastvold Pearl: Uveitis

Uveitis

Consensual photophobia is always a red flag!

Case: Pt presented to PMD earlier in the day, dx: conjunctivitis, sent home on topical abx, came to ED later that day for persistent pain.  L eye red, pt in considerable pain, photosensitive even when light shown in other eye, noticeable perilimbal or ciliary flush, anisocoria c affected eye more miotic, 1+ flare in anterior chamber on slit lamp, no fluorescein uptake, visual acuity wnl b/l, IOP < 20 b/l, no FB detected or mechanism, only some of the engorged vessels moved when brushed c Q-tip.

Dx: Uveitis

  1. Consensual photophobia
    1. Definition: severe pain in affected eye when light is shined in unaffected eye
    2. Cellular Flare
      1. Inflammatory cells in anterior chamber (on slit lamp)
      2. May cause blurry vision
      3. Miosis
        1. From ciliary mm spasm, will have anisicora and pain with accomodation (have them follow your finger close then far)
        2. How to evaluate anisicora (http://www.pacificu.edu/optometry/ce/courses/19433/pupilanompg2.cfm)
          1. Basically, note pupil size in the dark and the light, if this difference is constant, it’s physiologic
          2. Scleral Vascular Engorgement
            1. Conjunctival and episclera vessels move when touched with a Q-tip; the deep-seated scleral vessels do NOT
            2. Conjunctival and episcleral vessels blanch c topical phenylephrine gtts, scleral vessels do not
            3. Conjunctivitis: superficial vessel inflammation, Scleritis: deep vessel inflammation, Uveitis: both affected
            4. Ciliary Flush
              1. 2/2 dilation of radial vessels
              2. Often perilimbal flushing, whereas conjunctivitis has more peripheral conjunctival injection (uveitis on left below, conjunctivitis on right)

Book Stuff

Uveitis

  • Inflammation of the middle portion of the eye.
    • Anterior Uvea consists of iris and ciliary body = iritis (iris only) & iridocyclitis (both)
    • Posterior Uvea consists of the choroid - choroiditis, does not cause red eye but included for completeness purposes

Causes

  • Trauma (blunt or penetrating), corneal or scleral injury
  • Systemic microbial infection
    • Syphilis, brucelosis, herpes simplex, Lyme dz, TB
    • Immune-mediated
      • HLA-B27-associated diseases, sarcoidosis, JRA
      • Idiopathic in 50% of cases

Presentation

  • Red eye, unilateral in most cases
  • "Real" photophobia
  • Deep boring pain

Treatment

  1. Ophthalmologist referral within 24 hours
    • Topical steroids + intermediate-acting cycloplegics (i.e. cyclopentolate) for the ciliary spasm
    • Antibiotics not needed
  2. Expectant secondary glaucoma (often due to debris blocking normal drainage). Treat accordingly if IOP > 20.
  3. w/u can be performed by the ophthalmologist in an outpatient setting in 24 hrs, and may include a CBC, ESR, ANA, RPR, VDRL, PPD skin testing, lyme titer, etc.

ARDS

Although Lung protective ventilation has been demonstrated to significantly lower mortality in patients with ARDS, data regarding its use in patients without ARDS or  acute lung injury(ALI) has been scarce. The meta-anaylsis published in JAMA this month looked at patients receiving lung protective ventilation in patients without ALI or ARDS (6-8cc/kg IBW vs traditional ventilatory strategies with 10-12cc/kg IBW). The end points included, mortality, ventilator free days, development of acute lung injury/ARDS, pulmonary infection and atelectasis.

The most important thing to look at when reviewing this article is there is significant heterogeneity in the papers included, some randomized, others non-randomized, some in post-surgical/OR patients other medical patients and none in emergency department patients. Nonetheless, I like the results, and so I am passing the paper onto you to decide! 


1. Why is this topic important?
In patients who receive mechanical ventilation, acute lung injury and the development of ARDS are frequent complications associated with significant morbidity and mortality. The ideal ventilatory strategy is unknown, but the ARDSnetwork has demonstrated that lung protective ventilation in patients with ARDS reduces mortality, ICU length of stay, and pulmonary infections.  In the emergency department our ventilatory strategies may affect patient outcomes days down the road as lung injury has an insidious onset. Therefore the question remains whether in patients who are at risk for developing acute lung injury or acute respiratory distress syndrome benefit from the same lung protective ventilation early in the disease course i.e. beginning in the emergency department. 
2. What does the study attempt to show?
Three reviewers from the department of CCM in Brazil reviewed the available literature regarding the use of lung-protective ventilation in patients without acute respiratory distress syndrome, or acute lung injury (berlin definition of ALI and ARDS). Articles were selected if they evaluated two types of ventilation in patients without ARDS or ALI: low tidal volumes (6-8cc/kg IBW) vs. traditional tidal volumes (10-12cc/kg IBW). Studies included: prospective observational studies (before/after, cohort, cross-sectional), and RCT in a variety of settings. The study attempts to identify if lung protective ventilation is beneficial in all patients prior to the onset of ALI or ARDS.
3. What were the findings?
Twenty articles which included, with 2,822 participants analyzed.  Table 1 summarizes the characteristics of included studies, in which there was significant heterogeneity and none of the studies included began in the emergency department setting. Baseline characteristics were similar between the two groups except for several important ventilator characteristics: respiratory rate was higher in the low TV ventilation group (18 vs. 12) , while minute ventilation remained similar (8.6 vs. 8.4 L/min). The plateau pressure was lower in the low TV group although the mean Pplateau remained below 30 in both groups. PEEP was higher in the low TV group, and PaCO2 was also higher in the low TV group. See table 2 for all of the numbers. 
There was a decrease in lung injury development in the low TV ventilation group (RR 0.33 95% CI, 0.23-0.47 with a NNT 11), and a reduction in mortality in the low TV groups (RR 0.64, 95% CI 0.46-0.89; NNT 23.) The results were similar when you evaluated both randomized and nonrandomized studies.
4. How is patient care impacted?
In patients who require endotracheal intubation lower tidal volume ventilation is suggested by this meta-anyalsis to reduce both morbidity and mortality. This study included a wide-variety of patients including post-surgical, and medical patients. The intervention in this group is free, effective, and poses minimal risks to patients other than slight worsening in acidosis and increased PaCO2 which can be counter-balanced by increase respiratory rate and maintaining minute ventilation, and optimizing PEEP in order to reduce atelectasis. 

5. Is this an area of controversy?
Absolutely. Many physicians point to the fact that this is a summation of many non-randomized studies and studies in which potentially injurious lung volumes (800cc) were given to patients. In addition no prospective studies from the emergency department have EVER been completed. To complicate this issue in the emergency department the diagnosis of why a patient required endotracheal intubation is often obscured and the ability of an emergency physician to predict who may or may not develop acute lung injury is difficult if not impossible. 
Other physicians argue that low tidal volume ventilation increases atelectasis and in patients without ARDS this atelectasis may increase the risk of pulmonary infection, lower PaO2, and increase PCO2 worsening underlying acidosis, if present. 

6. Major limitations of the study?
This study is comprised of multiple prospective observational studies, non-RCT, in a heterogeneous population. Patients who are post-surgical are certainly at risk of developing ARDS, however the mechanism may be inherently different than that of a patient with septic shock. Since ARDS and ALI are clinical syndromes, and the pathophysiology for the causes is inherently different it is difficult to recommend one ventilatory strategies for all critically ill patients. 
My take on the study is that low tidal volume ventilation is potentially beneficial in all patients requiring mechanical ventilation. As long as you can manage the patients respiratory parameters with PEEP and RR while monitoring PCO2, pH, PaO2 and always keeping the plateau pressure < 30, all patients should receive lung protective ventilation. I believe this for several reasons, one of which is patients lungs who require intubation in the ED are not post-surgical they rarely are being intubated to be extubated in a few hours and we anticipate that intubation is going to be for days. Therefore, we should expect all of our patients to be at risk for ALI, and ARDS. In addition, the TV is not spread evenly throughout the lungs as the lungs often have a patchy distribution of injury, for example a LLL pneumonia means that region of the lung is filled with pus and the rest of the TV (which cannot reasonable aerate that portion of the lung) will be dispersed to the "healthy" lung possibly causing over distention and lung injury. 
Another important fact to remember is when assessing for lung protective ventilation it is based on IBW, so Jaba the hut gets ventilated based on height not weight! Rarely is a patient tall enough to require >600cc, but see the PDF in included for volume recommendations. 
The evidence is weak so read for yourself and be flexible to change as the evidence changes in the coming years, but for now I think it is reasonable to use lung protective ventilation in all emergency department patients requiring endotracheal intubation. 
-Dave
Neto AS et al.  Association Between Use of Lung-Protective Ventilation With Lower Tidal Volumes  and Clinical Outcomes Among Patients Without Acute Respiratory Distress Syndrome. JAMA 2012;308 (16): 1651-1659.

The Dispo of Patients with Upper GI Bleed

The goal for this JC was to discuss 2 commonly used scoring systems for patients with upper GI bleeds in an effort to identify patients who can be safely discharged from the ED. Both the Glasgow-Blatchford (GBS) and Rockall scores use clinical criteria, and the “full” Rockall also incorporates endoscopic findings.

Article 1: Stanley AJ, Ashley D, Dalton HR et al. Outpatient management of patients with low-risk upper-gastrointestinal haemorrhage: multicentre validation and prospective validation. Lancet. 2009;373:42-47.

This 2 part multi-center UK study used receiver-operating characteristic (ROC) curves to compare the ability of Glasgow-Blatchford (GBS) and Rockall scores (both pre and post-endoscopy Rockall) to predict need for clinical intervention (blood transfusion, endoscopic treatment, surgery) or death for 676 consecutive patients presenting with upper GI bleed. The area under the ROC curve was best for GBS (0.90 [95%CI 0.88-0.93), followed by full Rockall (0.81 [95% CI 0.77-0.84]), then pre-endoscopy Rockall (0.70 [95% CI 0.65-0.75]). In the second part of the study they prospectively identified 123 of 491 (22%) patients as low risk using a GBS of 0, of whom 84 (68%, or 15% of total cohort) were managed as outpatients, all without adverse events.

Bottom line article 1: A GBS of zero (BUN < 18, Hgb at least 13 for men/12 for women, SBP at least 110, Pulse < 100, absence of melena, syncope, CHF, liver dz) identifies a significant number of patients presenting with upper GI bleed who can safely be managed as outpatients.

Issues:

  • Not a biggie, but Blatchford was one of the authors.
  • In phase 2, only 40% of patients underwent outpatient endoscopy. They did have 6 month follow-up through chart review and contact with patient/PMD and verified no readmissions for GI hemorrhage or death.
  • Louis-UK study, did not include demographic data on patients, and missing endoscopy on large percentage of patients treated as outpatients.
  • McKean-wanted to see information about age (concern about sending home old patients) and other demographics. Needs more external validation, especially with diverse patient groups.


Comments from the sages:

Harwood: As residents move forward in their careers, there will be an increasing emphasis on conserving resources and saving money in medicine. GBS could be a useful tool used in a dichotomous fashion (“home or admit”) to avoid unnecessary admissions, but needs more external validation.

Rogu: Likes GBS-it’s easy to use. Also, developing decision instruments is usually a multi-step process: derivation study followed by a validation study and then an impact analysis. This is a nice example of a study that both validates the GBS decision instrument and in part 2 examines its clinical impact.

Kulstad C: Think about GBS like PERC: it's helpful in avoiding a work-up, but a positive shouldn’t be followed blindly disregarding the specific clinical situation.

 


Article 2: Stephens JR, Hare NC, Warshow U et al. Management of minor upper gastrointestinal haemorrhage in the community using the Glasgow Blatchford Score. Eur J Gastroenterol Hepatol 2009;21:1340-1346.

In this two part UK study, GBS was first prospectively calculated on 232 patients admitted to a teaching hospital with upper GI bleed in order to identify a low risk cut-off score. All patients were offered next day or emergent endoscopy as indicated. GBS ≤2 and age <70 successfully predicted favorable  outcome (no need for endoscopic therapy, blood transfusion or surgery, or death) in all 52 of 232 (22%) patients with this score.

They then used this cut-off (GBS ≤2, age <70) to prospectively identify 104 of a second cohort of 304 patients (34%) as low risk, and considered outpatient management of these patients. Importantly, only 32 of these 104 (31% of low risk group, 10.5% of entire group) were actually managed as outpatients. Low risk patients were still admitted if there were concerns about social situation/support, active comorbidities, if taking warfarin or had suspected varices. All patients managed as outpatients were offered next weekday endoscopy, and nearly all completed endoscopy. All low risk patients in this cohort (both those admitted and those managed as outpatients) had good outcomes-no need for interventions, no deaths. In addition, 91% of patients managed as outpatients expressed a strong preference for this option.

Important-lack of need for acute intervention does not equal lack of findings on endoscopy- outpatient management still mandates availability of next working day endoscopy.

This is also a small study, and didn't include sensitivity/specificity/confidence intervals, and should be replicated with more patients and in other patient populations.

Bottom line for article 2: by using a GBS ≤2 with an amendment for age < 70, a set of low risk patients with upper GI bleed (10% % in this study) can be identified for consideration of safe outpatient management, but next-day endoscopy must be available.

Issues:

  • As Erik often points out, there was no figure identifying how many potentially eligible patients were missed. If patients are enrolled M-F 9-5, the missed patients may constitute a different group with potentially different outcomes.
  • Janna: hard to set up endoscopy for all patients in our system. Liked that this approach reflects patient preference. Important observation in the study: rate of significant endoscopic findings dramatically increased with age (8% increase by decade of life).
  • Maletich: Even those admitted did well, although significant findings at endoscopy (18% vs. 9% findings in outpatient endoscopies)- reiterated challenge of outpatient endoscopy in US. This does help corroborate your decision to send some patients home.


Comments from the sages:

Harwood: Rockall score does not include hemoglobin. GBS includes hemoglobin. If one outcome measure is need for transfusion, then including hemoglobin introduces bias and favors your score.

Barbara: Treat seniors carefully!

Joan: NHS does not equal US health system-access to care and followup, availability of endoscopy much different.

 

Article 3: Chandra S, Hess EP, Agarwal D et al. External validation of the Glasgow-Blatchford Bleeding Core and the Rockall Score in the US setting. AJEM 2012;30:673-679.

In the last article, the authors attempt to externally validate the GBS and Rockall scores in the United States. In this retrospective study, 171 patients were identified with a diagnosis of upper GI Bleed. Primary outcome was need for endoscopic intervention, blood transfusion, angiography, surgery or death within 30 days. GBS outperformed pre-endoscopy Rockall (area under ROC curve 0.79 vs. 0.62), but was similar to post-endoscopy/full Rockall (area under ROC curve 0.72).

A GBS of 0 had a sensitivity of 99% (95% CI 93-100%) and specificity of 6% (95% CI 2-14%). For both the GBS and Rockall scores, at higher score cutoffs with greater specificity, the sensitivities were suboptimal.

Interestingly, 20 (12%) of cohort were discharged and managed as outpatients based on clinical gestalt, and only 2 required endoscopic intervention within 30 days (and no deaths), suggesting that EP decision making with appropriate consultation by GI is already safe and effective .

Bottom line for article 3: The prognostic accuracy of GBS and post-endoscopy Rockall were similarly high. Although the sensitivity of a GBS of 0 was excellent in this study, the low specificity of both GBS and Rockall prevents the authors from recommending either score as the sole means to identify patients safe for discharge/outpatient management.

Issues:

  • Matt: Limitations of retrospective chart review. Also, study only included residents of Olmsted County, as all inpatient and outpatient medical records for these patients are available through a searchable data set. This excluded a large number of otherwise potentially eligible patients.
  • Jako: This retrospective relatively small study alone not strong enough to support use of GBS, and low specificity limits usefulness. Needs external validation beyond one county in Minnesota.

Comments from the sages:

Sam: Low specificity means higher number of false positives. Clinical judgment may perform better. Trying to explain the poorer fit of the ROC curves in this study compared to study 1, likely in part due to the methods of chart review, eg if patients with a small amount of bleeding are diagnosed with “gastritis” and discharged, they wouldn’t be picked up and counted, and it’s a group that likely would be GBS 0 with excellent outcomes.

Stats blurb: Receiver Operating Characteristic (ROC) curves.
Y axis is True Positive Rate = True positives/All positives = sensitivity. X axis is False Positive Rate = False positives/All negatives = 1 – specificity.

The area under the curve is a measure of text accuracy and shows the tradeoff between sensitivity and specificity. The closer the curve follows the left-hand border and then the top border of the ROC space, the more accurate the test. A perfect test with a sensitivity and specific of 100% would have an area under the curve of 1.0 In general, 0.9 is excellent, 0.8 is good, 0.7 is fair, and 0.5 is a straight line at 45 degrees which is worthless. ROC curves are also often used to determine an optimal cut off value for a test. The optimal cut-off point on the curve will vary depending on whether the clinical situation demands a high sensitivity or high specificity.

Journal club bottom line:
The Glasgow Blatchford Score is easy to use and a score of zero appears to help predict a low risk group of patients with upper GI bleed who can be considered for outpatient management. A score of GBS ≤2 and age <70 is another reasonable cut-off, and incorporates age. Outpatient management for a patient with a GBS of 0 is only a safe option if excellent follow-up and next day endoscopy is assured. Respect age as a predictor of more serious underlying pathology and risk for bad outcomes-nobody in the room was comfortable sending home elderly patients with GI bleeds. And while the GBS is useful, it should be an adjunct to your clinical judgment: remember to consider co-morbidities and the social situation of the patient.

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.

Patient Satisfaction

The topic is a timely one, as Federal reimbursement will be linked to patient satisfaction scores starting in 2013.  Patient satisfaction is an important determinant of future health care utilization, treatment compliance, and willingness to return for care.  Patient satisfaction is also a significant contributor to your malpractice risk.

 

1.    Toma G, Triner W, McNutt L.  Patient Satisfaction as a Function of  Emergency Department Pre-Visit Expectations.  Ann Emerg Med. 2009;54:360-367.

 This cross-sectional study evaluated consecutive blocks of patients using a pre-visit patient expectation survey, and a post-visit patient satisfaction survey.  Their primary goal was to determine if meeting patients’ expectations improves overall patient satisfaction.  The surveys were self administered to consecutive patients during periods of block enrollment.  ED staff were not aware of the nature of the survey.  The initial survey asked about both diagnostic (blood test, Xray, ECG, etc) and therapeutic (pain meds, antibiotics, admission, etc) expectations, and the post-visit survey asked about overall satisfaction with the ED visit as well as other factors associated with satisfaction.  Demographic and treatment information was obtained from the patients’ charts.

 Of 987 eligible patients, 504 had complete information.  Interestingly, 29% of patients reported having no pre-visit expectations.  Overall patient satisfaction scores were high, with 50% being “very satisfied and 41% “satisfied”.  After adjusting for potential cofounders, there was no association between fulfilling patient expectations and patient satisfaction.  Instead, the measured factors with a strong impact on patient satisfaction were the physicians’ interpersonal skills, and to a lesser degree, adequate explanations of the diagnosis, the patients’ perception of ED waiting time, and the satisfaction with the time spent with the physician.

Limitations included the exclusion of very ill patients, some of the wording of the surveys (as Harwood pointed out, “expectations” and “investigations” might not be understood by all patients), Christine mentioned the large number of patients not enrolled, and it was also noted that the surveys were non-validated tools. 

 Dan G. asked the room about what specific behaviors are interpreted by patients as positive interpersonal skills.  Examples from the group:  sitting, appropriate touch, introductions/verbal gestures of respect, acknowledging everyone in the treatment room, apologies for long waits, asking if questions or anything else that can be done to make the patient comfortable, frequent updates on status, judicious use of COWS.

 

 2.    McCarthy M, Ding R, Zeger S, et al.  A Randomized Controlled Trial of the Effect of Service Delivery Information on Patient Satisfaction in an Emergency Department Fast Track.  Acad Emerg Med. 2011;18:674-685.

 Several past studies have concluded that patient perception of waiting time is more important than actual waiting time.  This RCT sought to determine if providing estimates of waiting room times and treatment times would increase overall satisfaction with care.   In this study, 1,011 patients triaged to Fast Track (80% of those eligible) during the day on weekdays were randomized to 3 groups:  usual care, receiving ED process information, or receiving ED process information + service delivery time estimates (50th and 90th waiting time percentiles).  Patients completed a brief survey at discharge describing their satisfaction with care, quality of information received, and timeliness of care. Neither of the interventions (receiving ED process information/service delivery time estimates) affected any satisfaction outcome.  Instead, satisfaction was significantly associated with actual waiting room time, and every 10 minute increase in WR time corresponded with an 8% decrease in the odds of reporting high satisfaction with care.  Satisfaction ratings also varied significantly among individual triage and fast track nurses and individual fast track doctors.

 As Shannon and Matt both commented, this article supports the concept that true patient experience matters more than expectations, although for this study expectations is defined by the information provided to the patients, rather than expectations patients had on arrival to the ED.  Matt also stressed the idea that individual medical care providers are all able to impact patient satisfaction scores.  Chintan displayed external PressGaney data suggesting that being kept informed is more a predictor than wait times, and both Matt and Christine noted that if the patients had been updated frequently rather than receiving waiting estimates one time at triage, they may have been happier.  Harwood described the “Disney Experience”; at Disney wait times are overestimated, and there are frequent markers along the way to let you know how much waiting time is left.  Also, using median wait times as an estimate as in this study is not ideal-providing inflated time estimates might have been more effective.  Kelly described the signage at Northwestern that provides generous estimates for all ED processes.

 

3.    Hickson G, Clayton E, Entman S,et al.  Obstetricians' Prior Malpractice Experience and Patients Satisfaction with Care.  JAMA. 1994 Nov 23-30;272(20):1583-7.

Finally, an oldie but a goodie.  From 1994, a landmark article-one of the first to test the hypothesis that when it comes to lawsuits, it’s better to be nice than to be good (ok, best to be both). 

The authors’ primary objective was to explore the relationship between physicians’ malpractice claims and patient satisfaction.  Obstetricians practicing in Florida between 1977 and 1983 were divided into four groups:  “No Claims” physicians had no malpractice claims during this time period.  “All Others” had a low level of claims, “High Pay” physicians were frequently sued and had large payments against them, and “High Frequency” physicians were sued frequently, but with overall low payments.  Birth records from 1987 were reviewed.  All cases of fetal/infant death and births with low Apgar scores were included, as well as a number of healthy births.  An independent firm conducted interviews using open and closed-ended questions of all available, consenting mothers.  A total of 898 interviews were included (63% response rate).  Patients of the Hi Frequency physicians were significantly more likely to state that they felt rushed, never received explanations for tests, and were ignored compared to the other physician groups.  Problems with physician-patient communication were the most frequently offered complaints.  Patients of No Claims physicians were consistently the most satisfied with their care. 

 Of interest, the No Claims and All Others groups included substantially more perinatal and neonatal deaths and therefore might have led to more negative feelings towards those doctors, yet patients of these physicians were more satisfied with their care.  Another hypothesis of why doctors are more frequently sued is that they provide technically inadequate care, however the authors abstracted a subset of medical records and found no significant differences in the technical care provided.

Janna pointed out the limitation that the interviews took place 5 years after the event, which may have biased or lessened the specific memories of the mothers.  The study also provided limited specific information about the physicians and their practices.  Finally, this is a study of obstetricians, however the results have good face validity and are likely able to be extrapolated to other specialties.

Ketofol

Ketamine/Propofol versus Single Agent for Procedural Sedation

 

Many thanks to Harwood and Michelle for hosting, and to our stellar presenters:
Tony, JoEllen, Brad, Vijay, Pikul and Mark.

By way of brief background, ED procedural sedation has evolved significantly over
the past 15 years. Back in the dark ages, our choices were benzo + narcotics, chloral
hydrate, or methohexital. Then ketamine gained popularity in kids, etomidate
made the leap from induction agent to procedural sedation drug, and most recently
propofol joined the game. As procedural sedation became more sophisticated,
one idea that has gained traction over the past 5 years is to mix ketamine and
propofol. Intuitively, it makes sense: propofol is anti-emetic and may smooth out
ketamine’s emergence reactions, but can cause significant respiratory depression
and hypotension. Ketamine has analgesic properties, and maintains respiratory
reflexes and blood pressure, but can cause nausea and bad trips. The combination
might allow decreased dosing of both agents and mitigate the side effects of each.

Article 1:
Andolfatto G, Willman G. A Prospective Case Series of Pediatric Procedural
Sedation and Analgesia in the ED Using Single-syringe Ketamine-Propofol
Combination (Ketofol). Acad Emerg Med. 2010;17:194-201.

In this article, the authors describe a prospective case series of 219 pediatric
patients who received ketofol for procedural sedation (majority orthopedic
procedures), examining effectiveness, recovery time, and adverse effect profile.
Physicians used a single syringe technique, with a 1:1 mixture of 10 mg/ml
ketamine and 10 mg/ml propofol. Titrated aliquots of 0.5 mg/kg ketofol (0.5 mg/kg
each of propofol and ketamine) were given at 30 second to 1 minute intervals at the
discretion of the treating physician. The median dose of medication administered
was 0.8 mg/kg each of ketamine and propofol, with a median recovery time of 14
minutes. Less than 1% of patients experienced unpleasant emergence requiring
treatment, although nearly 3 % of patients had unpleasant CNS symptoms.
Regarding airway events, 1.4% of patients required either stimulation or brief BVM,
and several other patients required airway repositioning. No patients vomited
during or after sedation. Procedural sedation was considered successful in all
patients, and patient/caretaker/medical provider satisfaction was high.

This was basically a “Mikey liked it” study, or as JoEllen described it, a marketing
study, without the methodologic rigor of a RCT. Children less than 1 year of age
were excluded, and there were few children included who were younger than 2.

The study was subject to selection bias, as physicians chose when to use ketofol and
when to choose a different agent. As there was no comparison arm, the authors
compared medication doses, recovery times and complications to published rates
for ketamine and propofol from past studies. In this regard, ketofol performed well,
with lower dosing, and improved emesis rates and recovery times compared to
ketamine, although demonstrating similar airway and emergence phenomena rates
to ketamine alone.

Article 2:
Shah A, Mosdossy G, et al. A Blinded, Randomized Controlled Trial to Evaluate
Ketamine/Propofol Versus Ketamine Alone for Procedural Sedation in
Children. Ann Emerg Med. 2011;57:425-33.

This trial has significantly improved methodology as compared with the Article
#1, as it is a blinded RCT. In this study, 136 children with isolated orthopedic
injuries were randomized to receive either 0.5 mg/kg ketamine and 0.5 mg/kg
propofol (K/P), or 1.0 mg/kg ketamine + intralipid placebo (K). These were
also the median doses of each medication administered. If additional sedation
was needed, the K/P group received extra propofol, and the K group received extra
ketamine, again in a blinded fashion. More patients in the K/P ended up needing
extra medication (more propofol). Their primary outcome, total sedation time,
was clinically not significant between the 2 groups (K/P 13 minutes, K 16
minutes), although it was statistically significant. There was 10% less vomiting
and 5% fewer unpleasant recovery reactions in the K group. Airway adverse
events were similar between the 2 groups, as was median total sedation time
and time to recovery. No patient in either group required BVM or other airway
intervention besides airway repositioning or supplemental oxygen. Medical
provider and patient satisfaction scores favored K/P, although confidence intervals
were wide. Methodology pearl: it was discussed that sedation time is a curious
choice of primary outcome, however it is an outcome measure that can be powered
to achieve a statistically significant result, as opposed to serious but rare adverse
complications.

Article 3:
David H, Shipp J. A Randomized Controlled Trial of Ketamine/Propofol Versus
Propofol Alone for Emergency Department Procedural Sedation. Ann Emerg
Med. 2011;57:435-441.

In this blinded RCT, 193 ED patients, both adults and children, received either
ketamine 0.5 mg/kg + propofol 1.0 mg/kg (K/P) or placebo + propofol 1.0 mg/
kg (P). All patients received fentanyl 5 minutes before sedation. Additional bolus

doses of 0.5 mg/kg of propofol were given as needed to both groups. There was
no statistically significant difference in the primary outcome of respiratory
depression between the 2 groups (K/P 22%, P 28%), although as Erik pointed
out, the study was underpowered for their primary outcome, implying a 20% risk
of a Type II error (false negative results, or beta error). Erik also mentioned the
common methodology mistake illustrated in the fishbone diagram describing study
flow, which does not identify the number of patients who were eligible for the study
but not approached about enrollment. This threatens the study’s internal validity.
For both groups, the only airway interventions required were either BVM or a
jaw thrust.

Secondary outcomes were provider satisfaction, sedation quality and total propofol
dose. There were no emergency reactions or serious adverse events identified
in either group. Physician/nurse satisfaction favored K/P, although as Andrea
pointed out, they didn’t assess patient satisfaction. There was likely also
incomplete blinding. There was a slight trend towards improved sedation quality in
the K/P group using their pain scale, although this was not statistically significant.

 

SUMMARY:

There was a fair amount of healthy discussion at the end of journal club about
attending preference and experience, both with single agents and with ketofol.
For Dan G, ketofol has revolutionized procedural sedation. Harwood is certainly
a super-user of ketofol, and believes that the literature supports improved patient
and provider satisfaction with ketofol over either agent alone. He prefers the
nuanced approach of maintaining each drug in its own syringe, to maintain dosing
independence and compensate for the different pharmacokinetics. Andrea is
concerned about the emergence phenomena associated with ketamine, and doesn’t
accept the concept of sub-dissociative dosing of ketamine, or that by giving lower
doses of ketamine you provide analgesia and avoid bad trips. She certainly uses
ketamine and ketofol, but prefers propofol, with additional narcotics as needed
for analgesia. Mike Lambert also likes the Michael Jackson drug. Others in the
room (me) prefer straight ketamine over ketofol for pediatric procedural sedation.
Effectiveness and recovery times are clinically similar for combo versus single
agent, and although side effect profile trends towards favoring ketofol, differences
are small with wide confidence intervals. I don’t see the benefit of 2 drugs over one,
except in older children/adults who are at more risk of emergence reactions…then I
add propofol. I avoid ketamine in children who are very anxious from the start, and
work to establish a calm/comfortable induction environment.

So, residents, just memorize all your attendings’ preferences. Or, better yet, as
pointed out that night, learn how to use a number of different procedural sedation
medications. Different agents may be more appropriate for different situations,
and depending on where you eventually practice, your choices may be restricted by
hospital regulations.

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.