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

Resuscitation for Vfib arrest

Clinical Scenario and PICO question

You have finally gotten away from work for a week to take that ski trip you have been planning.  Waiting for the chairlift you see a bearded skier, with equipment and an outfit straight out of 1972, collapse. You look around desperately for Ski Patrol in hopes of avoiding the taint of work on your hard-earned vacation, but to no avail.

The teenage snowboarder with the pierced nose uses his iPhone 4 to call 911 and tells you an ambulance is “totally” en route, ETA 10 minutes. What do you do? Do you really want to start mouth to mouth on this bearded antiquity? When EMS arrives, should they defibrillate immediately?

 PICO question

P: Patient with V-fib cardiac arrest, prolonged ambulance response time

I:  Compression only CPR; Delayed defibrillation after CPR by EMS

C: Compression and ventilation CPR; Immediate defibrillation by EMS

O:  Return of spontaneous circulation, Survival to hospital discharge, Neurologic outcome

Synopsis

A big thank you to hosts Mike Lambert and Hannah Watts.  Shout outs to Tyler, Vijay, Jesse, Matt, CDO and Mark for their thoughtful and entertaining presentations.

Article #1

Rea TD, Fahrenbruch C, Culley L, et al.  CPR with Chest Compression Alone or With Rescue Breathing.  NEJM 2010;363:423-33.

This is the second large RCT published in the same issue of NEJM on this topic (both with same conclusions).  In this multicenter, RCT of dispatcher instructions to bystanders performing CPR on patients after cardiac arrest, 981 patients were randomly assigned to receive chest compressions alone, and 960 to receive chest compressions plus rescue breathing.  The entire resuscitation was taped, with the dispatcher coaching the bystander through the resuscitation until EMS arrival.  There was no significant difference between the two groups in the primary outcome,  survival to hospital discharge (12.5% with compressions alone, 11.0% with compressions plus rescue breathing, P=0.31).  There was also no difference between the 2 groups for the secondary outcome of favorable neurologic outcome at discharge (14.4% and 11.5%, respectively; P=0.13).  In other words, in this study, compression only CPR was as effective as compressions plus rescue breathing, and didn’t save lives at the expense of neurologic outcome (in fact trend towards improved neurologic outcome with compressions alone).  

Consensus in the room was that this was a methodologically sound study.  Majority of patients were enrolled in Seattle, where your chance of survival after cardiac arrest is near miraculous anyway.  Approximately 34% of patients were enrolled in London (London patients had a 4% survival rate).   There is a threat to external validity because of the variation in CPR training/post-arrest survival in different areas of the country and the world, but conceptually, compression only CPR should be even less intimidating to bystanders in areas of low-community CPR training rates (everywhere outside Seattle).  As an illustration of this, in the study, patients randomly assigned to receive chest compressions alone were more likely to actually receive those compressions than patients randomized to compressions + rescue breathing (80.5% vs. 72.7%, P<0.001).   

A few small methodology issues:  CPR guidelines changed in 2006 (during this study), and differences between the 2 groups might be smaller with the newer recommended 30:2 rather than 15:2 ratio of compressions/ventilations.  Also, there was no controlling for differences in ACLS interventions, therapeutic hypothermia, etc.  Also, nice point Harwood, some patients were excluded because when EMS arrived, they were found not be in arrest.   Maybe some of those who received rescue breathing came out of arrest, and then therefore were excluded (bias against rescue breathing). 

A bone for the Bayesians in the audience:   Erik pointed out that the conclusion paragraph of the abstract contained the statement that there was a trend towards better outcomes in certain subgroups.  The idea of stressing point estimates and giving value to trends rather than defining meaningful conclusions only as those with  p values less than 0.05 represents an important and recent change in editorial philosophy.

This study did contain 4 pre-specified subgroup analyses.  There was a trend towards improved outcomes with chest compressions alone in patients with arrest from a cardiac cause, and a trend towards improved outcomes with chest compressions + rescue breathing for patients with non-cardiac causes of arrest.  While it might be tempting to start giving different CPR instructions to bystanders  treating patients with different etiologies of arrest, subgroup analyses should not be viewed as reliable conclusions, but only as ways to generate future hypotheses.  An important exception was discussed-the pediatric patient in arrest.  All 3 JC studies excluded children, and it’s well known that children have much higher rates of respiratory arrest, and therefore should receive both compressions and ventilations. 

This study highlights the difference between efficacy and effectiveness.  The efficacy of a drug is the measure of a drug’s ability to treat a certain condition (ideal, or study world).  The effectiveness of a drug takes into account real world factors such as tolerability and ease of use.  We anticipate that regardless of the efficacy of compression only CPR, the effectiveness should be significant, as bystanders reluctant to perform mouth-to mouth rescue breathing may be more willing to jump in and perform CPR if compressions are all that is required.  Interestingly in this study, they performed efficacy analyses, and the magnitude of differences favoring chest compression alone was larger than that observed in the effectiveness analyses.  In other words, something about compression only CPR (e.g. fewer interruptionsàimproved circulation) appears to be beneficial, beyond the effectiveness issue of reluctance to perform rescue breathing.

In 2008, the AHA published a “Call to Action”, emphasizing the importance of high-quality chest compressions.  Unless bystanders are trained and comfortable with rescue breathing, it is recommended to call 911 and then simply provide hard and fast compression only CPR with minimal interruptions until EMS arrival (Circulation 2008;117:2162-2167).   This recommendation is limited to arrest in adults presumed to be of cardiac origin.  A current billboard and public service announcement campaign is promoting this recommendation.

Article #2:

Wik L, Hansen TB, Fylling F et al.  Delaying Defibrillation to Give Basic Cardiopulmonary Resuscitation to Patients with Out-of-Hospital Ventricular Fibrillation.  JAMA 2003;289:1389-1395.

Switching gears, the second topic discussed was the concept of delaying defibrillation for several minutes to first perform high-quality CPR.   The concept here is that ventricular fibrillation is a huge energy suck (resulting in a low ATP, severe acidosis state).  If tissue perfusion can be improved by performing high quality CPR for several minutes, defibrillation may have a higher chance of success. 

In this RCT of 200 patients with out-of-hospital ventricular fibrillation arrest in Oslo, Norway, patients either received standard care with immediate defibrillation, or “CPR first” with 3 minutes of CPR by EMS personnel prior to defibrillation.  The CPR first group also received more prolonged CPR prior to subsequent defibrillations.  Their primary end point was survival to hospital discharge.  Survival for the standard group was 15% versus 22% in the CPR first group (P=0.17, not significant, but trend favoring CPR first).  The secondary outcome of good neurologic outcome at hospital discharge also demonstrated no significant difference between the two groups.   A pre-specified subgroup analysis evaluated outcomes in patients with ambulance response times of up to or longer than 5 minutes.  For patients with ambulance response times greater than 5 minutes, hospital and one year survival were statistically better in the group who received CPR first prior to defibrillation.  Again, this was sub-group analysis (hypothesis generating) with small subgroups, and as Erik mentioned, small sub-groups lead to an even higher chance of not seeing these results replicated in future trials.  

Other methodologic issues:  as Christine pointed out, this study was performed back in the day of stacked shocks.   Initial CPR wasn’t just priming the pump:  multiple defibrillation attempts in the standard group meant significantly less CPR, and might have affected the study outcomes (favoring CPR first).   Harwood also pointed out his favorite pet peeve; in this article published in JAMA, “the numbers don’t add up”.  Probably not a fatal flaw, but come on…get the tables right!

There were a similar number of witnessed arrests (>90%) and bystander CPR being performed prior to EMS arrival (about half) in both groups.  While bystander CPR is often ineffective, this study didn’t (couldn’t) measure the quality of CPR performed before EMS arrival, and therefore these results might be quite different if high-quality CPR was provided by bystanders.

In the future, whether defibrillation should be postponed in favor of immediate CPR may depend on the frequency spectrum of the electrocardiogram as this can predict the probability of ROSC after defibrillation-stay tuned.

So, no difference overall, but results favoring CPR first in situations with prolonged ambulance response times, based on sub-group analysis.  Whether these results hold up in other studies, and how long CPR should be performed prior to defibrillation all need to be investigated.  There was disagreement in the room about whether or not to defibrillate the scenario patient immediately, but it was agreed that aggressive CPR should be performed while the defibrillator is being prepared.

A final important point about witnessed VT/VF in-hospital arrests or witnessed out-of-hospital arrests when an AED is immediately available.  Shock them.  Shock them right away.  Do not intubate them first.  Do not delay defibrillation to perform CPR.  Shock them immediately.  Shock them now.

Article #3:

Baker PW, Conway J, Cotton C et al.  Defibrillation or CPR first for patients with out-of-hospital cardiac arrests found by paramedics to be in ventricular fibrillation? Resuscitation 2008;79:424-431.

Last and least, the most recent RCT on the topic of CPR before defibrillation in VF cardiac arrest.  In this Australian study, a total of 202 patients with out-of-hospital VF arrest were randomized to receive either 3 minutes of EMS CPR prior to defibrillation, or immediate defibrillation.  Primary outcome was survival to hospital discharge, and secondary outcomes included neurologic status at discharge.  The study was powered to detect the outcome difference found in the Wik study for patients with an ambulance response time of >5 minutes.  In this study, for all response times combined, as well as for the group with ambulance response times >5 minutes, there was a tendency for reduced survival to hospital discharge in the CPR before defibrillation group (lower by 6.8% and 4.7%, respectively), although these were not statistically significant. 

There were significant problems with this study.  First, it was stopped early, but you had to discover this in the discussion section, which is weird and suspicious.  Second, they performed at per-protocol, rather than an intention to treat (ITT) analysis.  ITT analysis is based on initial treatment intent, not treatment eventually received.  For the purposes of an ITT analysis, everyone who begins the treatment in a trial is considered to be part of the trial, regardless of whether or not they finish the trial or crossover to another treatment.  This helps to prevent erroneous interpretation of the results.  In addition, 139 patients were “not randomized by mistake”; a significant number of patients excluded and no further explanation provided. 

In sum, a negative study (against CPR prior to defibrillation) with significant methodologic flaws.  See Article #2 for our JC group’s bottom line.

The one interesting and unforeseen conclusion from this study:  it took place between 2005 and 2007, and the protocol changed mid-study to reflect the new international CPR guidelines published in 2006.  Overall survival in this study increased more than two-fold following introduction of the 2006 guidelines (8.8% to 18%).  Although this was not statistically significant, it is a positive trend in survival and indirectly supports the concept of aggressive CPR with minimal interruptions for patients with cardiac arrest.

The most recent AHA guidelines (2006) give very wishy-washy recommendations on CPR first before defibrillation for out-of-hospital arrest not witnessed by EMS (“may consider”, “may give” CPR before defibrillation).  This reflects the conflicting evidence on the topic.  The new AHA CPR and Emergency Cardiovascular Care guidelines are due out in February 2011.  

Syncope and Clinical Decision Rules

Clinical Scenario and PICO question

Fresh from med school, you nervously approach your 1^st ED shift.  Your 1^st patient is Mr. Jones, a very active 80 y/o.  He enjoys tennis, golf, biking, boating, cards & spending time with his buddies, wife, siblings, children & grandchildren.  His wife provides the following eyewitness account.  Mr. Jones was preparing to hang a picture.  His wife heard a metal clank & turn to see his tape measure falling from his open hand & bouncing on the floor.  Mr. Jones was simply collapsing/falling backwards & Mrs. Jones couldn’t catch him in time.  He fell & hit the back of his head on the wooden floor.  Mrs. Jones ran over & found him unresponsive (no Sz activity), with a little blood coming from the back of his head.   She went to the phone & called 911.  Less than 60 secs later, she was back @ his side.  He was sitting up holding his head.  He had no idea what had happened & says he’s been “fine” since.

Mr. Jones’ ED exam was normal, including VS’s, P.Ox, no cardiac murmurs, no signs of CHF & heme (-) stool on rectal exam.  PMHx is “healthy a horse” with only HTN.  Meds = Lopressor-HCT (25/50 HCTZ-metoprolol) + 81 mg ASA/day.

CXR, plain CT head/neck, CBC, chemistries, & cardiac markers are (-).  BNP is 250.  EKG is identical to EKG from 2 years ago à NSR @ 72, with normal PR, QRS, QTc intervals & LVH.

Mr. Jones receives 1000 mg acetaminophen, Td, & 5 staples to his scalp.  4 hrs after his fall, he has had no dysrhythmias, & he wants to go home.  The ED faculty & his wife prefer admission.  When contacted, his PMD say, “I don’t like that story.  Get him admitted to a tele-bed.  My admits are covered by Dr. Hospitalist, so call him.”

Dr. Hospitalist declines the admit and launches into a prolonged explanation that includes, “My last 50 syncope admits got tele for 1-2 days, nothing ever happened & they all went home.”  “I find it amusing the ED doesn’t even know your own literature.”  “If you apply the SF Syncope Rules to Mr. Jones, he can be safely D/C from the ED.”  “If there is any additional concerns, his PMD can arrange an outpatient Holter monitor.”

When apprised of the conversation, your ED faculty parries, “Hey, I know the EM literature enough to know that the SF Syncope rules don’t work; they miss 10% of bad outcomes.  Plus isn’t there that new ROSE Syncope Rule that says to admit for elevated BNP.  Call the Hospitalist back.”  You find the Rose (Risk Stratification of Syncope in E.D.) study on line & discover Mr. Jones’ need a BNP of 300 for admission.  Your EM faculty solves the dilemma by suggesting, “Order a tilt test, a 2^nd Troponin & 2^ndBNP.  We’ll sign Mr. Smith out to the next team.”

Unfortunately, Harwood is part of the oncoming team & declines your sign-out plan.  “This guy needed admission 8 hours ago.  We’re not going to wait for more bogus testing.”  He suggests the EM faculty simply call Dr. Hospitalist & get Mr. Smith admitted.  “Mr. Jones meets ACEP & ESC (European Society of Cardiology) syncope admit criteria.  If you need literature, give Dr. Hospitalist the STePS (Short-Term Prognosis of Syncope) study or OESIL (Osservatorio Epidemiologico della Sincope nel Lazio).”

Your 1^st shift is almost over & you haven’t even gotten your 1^st Pt admitted.  You realize this residency thing isn’t as easy as the EM-3’s make it look.  Before you switch to a career in Pathology, you decide to read the Journal Club articles.  Still, you wonder:

1.   Is there a difference between a “Decision Rule”, a “Prediction Instrument”, a “Clinical Prognostic Model” and a “Guideline”?

2.   Are any of these decision tools worth using?

3.   If so, how do you tell the good “Decision Tools” from the bad ones?

P:   80 y/o male with syncope.

I:    ED discharge (based on a decision tool).

C:   Hospital admission.

O:  “Bad” outcomes in 7 &/or 30 days

Synopsis

Thanks to Harwood and Michelle for a bucolic mid-summer’s evening .  Also, excellent synopses and discussions by JoEllen, Gromis, Abbi, Nelson, Yenter and Ben.  The topic for Journal Club this month was decision rules; actually better described as decision instruments or tools, as they exist to augment, but never to replace physician judgment. 

The development of a decision tool should answer the following 6 questions:  Is there a need for the tool?  Was the tool derived according to sound methodologic standards?  Has the tool been prospectively validated and refined?  Has the tool been successfully implemented into clinical practice?  Would use of the tool be cost effective?  How will the tool be disseminated and implemented?

As an example of a prevalent presenting complaint that is often harmless but occasionally associated with significant morbidity or death (“low-risk, high-stakes”), we examined 2 decision instruments for syncope. 

The San Francisco Syncope Rule derivation set results were published in 2004 in the Annals of Emergency Medicine, and at the time the rule was considered a possible game-changer for syncope.   The goal of the SF Syncope Rule is to identify ED patients with syncope or near syncope who are at low risk for short-term (7 day) serious outcomes, allowing clinicians to potentially send home low-risk patients safely.  Sensitivity of the rule in the derivation cohort was 96% (95% CI 92%-100%) and specificity was 62% (95% CI 58%-66%). 

Our first article was:

1.    

 1. Quinn JV, McDermott DA, Stiell IG, et al.  Prospective validation of the San Francisco Syncope Rule to predict patients with serious outcomes.  Ann Emerg Med. 2006;47:448–53.

In this study, the authors prospectively validated the SF Syncope Rule, evaluating 791 consecutive visits in adults for syncope, excluding patients with clear drug/trauma/alcohol/seizure associated syncope, or with altered mental status or new neurologic deficits.   Patients were predicted to be at high risk for an adverse short-term outcome if they met ANY of the following criteria:  history of CHF, Hct <30%, abnormal ECG (non-sinus or any new changes), Shortness of breath, or triage SBP <90.   The rule is often remembered by its mnemonic CHESS.  In this validation cohort,  sensitivity/specificity was based on serious outcomes that were undiagnosed during the ED visit.  Short-term serious outcomes included death, MI, arrhythmia, PE, CVA, SAH, significant hemorrhage/anemia, procedural interventions and re-hospitalization.  Sensitivity was 98% (95% CI 89%-100%) and specificity was 56% (95% CI 52%-60%). 

So what’s the problem?  Well, from a standpoint of decision rule development, one concern is that the same group both derived and validated the rule in the same (single) institution, raising concerns aboutexternal validity-how will it perform in another patient population?  From an internal validitystandpoint, there is no “fishbone” diagram-no accounting of how many patients were eligible for the study, how many were actually enrolled, why some weren’t enrolled, etc.  Gromis made the interesting point that patients meeting one of these criteria for high risk are already a high risk population-they could come in with an ankle sprain, and still have a risk for a serious cardiac or neuro outcome in the following 30 days-does this really help differentiate low/high risk patients, or are the factors in the rule just obvious common sense?  Second point from Gromis-there is no sensitivity analysis in the article.  Sensitivity analyses are key methodologic features of a paper wherein the authors re-analyze their data with different assumptions-what if there was one additional bad outcome which was missed?  What happens if all the lost to follow-up patients had bad outcomes…or good outcomes?  Small changes in missing or incomplete data can change the results dramatically, and this should always be discussed in the manuscript.  Miscalculating one bad outcome in this study easily drops the sensitivity of the rule to the low 90s, with lower CI limit in the 80s. 

Also, although ED physicians in this study made their own decisions about admission/discharge/management of the study patients, the physicians were filling out data forms, and were very aware of the rule and the study.  Significant bias was likely introduced with regards to management decisions because of this foreknowledge.  There was also probably a Hawthorne effect, with the patients’ overall care and possibly outcomes improving simply from everyone knowing about the study and making small, even unrecognized changes in care. 

There was also no “Table 1” in this paper; the initial chart documenting all of the demographic information about the patients in the study-key to comparing patient populations within and between studies.  Harwood asked the provocative question of when audience members are comfortable (or at least don’t feel physically ill) when they hear that one of their ED patients has died.  Is it at 7 days as in the derivation set?  Thirty days as in this validation set?  Longer?  Changing the outcome follow-up time changes one’s perspective.  As Sean said, maybe it’s just most important that the patient gets the appropriate workup, and if that is facilitated in a few days and then the patient has a bad outcome, you can at least feel that everything appropriate was done.  Ultimately, for syncope (and for other symptoms associated with possible badness), the importance of a rule is not in defining who needs to be admitted, but in defining who needs an appropriate and timely workup.

2. Birnbaum A, Esses D, Bijur P, et al.  Failure to validate the San Francisco Syncope Rule in an independent emergency department population.  Ann Emerg Med. 2008;52:151–9

Several studies have since been published questioning the high sensitivity initially reported for the SF Syncope Rule.  Birnbaum’s study in 2008 tested the SF Syncope Rule in 713 prospectively enrolled patients with syncope or near syncope.  They used the same inclusion, exclusion, and serious outcome definitions as the original derivation trial, as well as the original 7 day follow-up time.  It only included adults, whereas the original derivation/validation studies included children (changing expected sensitivity).  This study did provide a (nearly complete) fishbone diagram, as well as a Table including demographic specifics on the patients.  Physicians again were aware of the study and responsible for data collection, likely introducing bias.  A sensitivity analysis was performed, and making assumptions about missing data that would maximize the performance of the rule made no significant differences in the rule’s sensitivity.  In this study, the sensitivity of the SF Syncope Rule in predicting 7 day serious outcomes was 74% (95% CI 61% to 84%) with a specificity of 57% (95% CI 53%-61%).   This analysis was for serious outcomes, whether recognized in the ED or in the following 7 days.  Harwood made the point that what we care about are decision instruments that identify bad outcomes that are not obvious in the ED.  If someone has a GI bleed and happens to pass out, the primary admission diagnosis is GI bleed, not syncope-we don’t need help identifying those patients.   The authors of this paper performed a post hoc analysis of serious outcomes not identified in the ED, and the SF syncope rule performed even more poorly; sensitivity 68%.  Looking at the usefulness of the rule in another way, as Dan Nelson pointed out, from this study the negative likelihood ratio of 0.5 will influence the change from your pre to post test probability of a serious outcome by only a very limited amount.  Interestingly, the majority of serious outcomes missed by the rule were arrhythmias. 

3.  Reed MJ, Newby DE, et al.  The ROSE (Risk Stratification of Syncope in the  Emergency Department) Study.  J Am Coll Cardiol. 2010;55:713–21. 

Finally, a brand new syncope decision instrument, published in 2010.  What’s new and different about this tool?  First, it is a way excellent 9 page advertisement for BNP (my bias, although Biosite provided the test strips, the point of care machine, and paid for the author to travel to Spain to present the results).   The authors studied about 550 patients in a derivation cohort, and about 550 patients in a validation cohort (results of both reported in same study).  In each case, this was a little more than half of the potentially eligible patients-they missed a bunch of eligible patients, and the death rate was slightly higher in the non-enrolled patients.   Their tool, with the mnemonic BRACES, recommends admission if a patient has any of the following:  BNP >300, Bradycardia with HR <50, Rectal exam heme +, Anemia with Hct <9, Chest pain, ECG with Q waves, Saturation </= 94% on room air.  The authors reported an “excellent” sensitivity of 87.2% in the validation cohort to predict 30 day serious outcomes (specificity 65.5%).  No confidence intervals reported anyplace, so who knows how much higher your risk is than simply missing 1 in 10 bad outcomes.  No demographic information on the patients, no sensitivity analysis.  As often happens, the sensitivity dropped from 92.5% in the derivation set to 87% in the validation set…..what happens when it’s externally validated down the road?  Likely further reduction in sensitivity.  The authors use a lot of ink to discuss how great BNP was at predicting badness, although used alone it only picked up 41% of serious outcomes (an “excellent” predictor per the authors).  BNP increases with age, so could it be that BNP is just a surrogate for increasing risk in the elderly (order a BNP, or as Erik does, just ask the patient how old they are).  One small pro-BNP point-in this study they didn’t see the large number of missed arrthymias(they missed other things instead).  Maybe there’s some utility in  ordering the BNP in selected patients as an additional screen for higher risk, but this study doesn’t answer that question.  

As Vijay very reasonably asked at the end of the evening-so now what?  Neither of the reviewed syncope decision tools works well, and we still have 1% of our ED patients presenting with syncope, and approximately 4-6% of them will have serious short term outcomes not identified in the ED.  For the residents, first, it’s a reminder that medicine’s not easy.  It’s not all algorithms and checklists, but that’s also some of the beauty and joy of clinical practice (JoEllen said it better).   Channeling Harwood, if you use one of the syncope tools, especially SF, and it’s positive, you have a slam-dunk admission.  If the tool is negative, talk it over with your attending. EBM is ultimately a joining of the published evidence, clinical expertise, and patient values-having a few years of experience helps.  Andrea added an important point-remember that prior workup matters, and a prior history of benign syncope in an individual matters.  Also, the value of decision tools lies not only in their rote application, but in recognizing that the components of the tool are individually high-risk factors, and can be used to help develop your own clinical judgment.  Being familiar with the Ottawa ankle rules reminds me which parts of the ankle exam to really focus on.  As several in the audience pointed out, syncope is a complex presenting complaint, and therefore may not lend itself to the easy development of a decision instrument.  However, new rules for a variety of complaints are being rolled out every month, and understanding how to critically appraise articles describing new decision tools is crucial to helping you separate the Leatherman Wave from the Bassomatic.

TIAs

Timing of the Evaluation of TIAs

Over the past 10 years, a number of studies have established a one-week risk for CVA of up to 10% after a TIA, with up to half of those CVAs occurring in the first 2 days.  Given this high risk of completed CVA, we sought to examine 3 questions:  is there an accurate and simple clinical scoring system which helps identify patients at high risk of early CVA after TIA?  Does urgent evaluation and treatment of TIA improve clinical outcomes and decrease the risk of CVA after TIA?  Is an ED observation unit accelerated diagnostic TIA protocol feasible, efficient, and cost-effective?

1.  Asimos AW et al. A Multicenter Evaluation of the ABCD2 Score’s Accuracy for Predicting Early Ischemic Stroke in Admitted Patients With Transient Ischemic Attack. Annals of Emergency Medicine. 2010;55:201-210.

This large multicenter study of 1667 patients evaluated the ability of the ABCD2 score (age, BP, clinical features, duration, diabetes) to predict 7 day risk of CVA in patients admitted to the hospital within 24 hours after TIA.  This was a convenience sample, and although billed as a prospective study, actually retrospectively examined the patients’ charts.  Therefore ABCD2 scores were unavailable for almost 35% of patients.  Although they attempted to impute (estimate and fill in) missing data based on other observed variables, this still limits the study’s internal validity.  Twenty-three percent of patients were diagnosed with CVA within 7 days,  in part reflecting that the study only included admitted patients (many minor TIAs sent home).  Most CVAs occurred in the first 2 days.  The c statistic (=area under the ROC curve) was 0.59 for the risk of any ischemic CVA in 7 days, and 0.71 for disabling CVA within 7 days.  In other words, the ABCD2 score poorly predicted the risk of ischemic CVA, and was better but still not great at predicting disabling CVA.  The sensitivity of a low ABCD2 score (</= 3) was only 87% for identifying patients at low risk for CVA in 7 days (sensitivity was 96% identifying low risk for disabling CVA, CI 88-99%).  

Their definition of “disabling CVA” was Modified Rankin Scale score of greater than 2, which implies a degree of dependence.  Point was made that a MRS score of 2, although “mild,” still means that a pt is unable to do everything they were capable of before the CVA, eg maybe an EP couldn’t practice emergency medicine.  For us, that would be a pretty devastating CVA, so most people in the room wanted a score that is really good at predicting all CVAs, not just “disabling” ones.  Other points of conversation:  tremendous variability in the admission rates for TIA in the participating hospitals (35-100%) and no standardized work-up or treatment plans-really heterogeneous study.  They chose patient oriented outcomes (clinical TIA/CVA) rather than disease oriented outcomes (MRI findings) which is laudable, but there is an inherent difficulty in defining TIA vs. CVA early in the presentation (are some early TIAs really CVAs…probably yes).  We also don’t know when patients received MRIs and this is a problem since the natural history of MRI changes very early in TIA/CVA has yet to be well defined. 

Bottom line:  ABCD2 score not sufficiently accurate in this study to use it to predict short-term risk of CVA.  Also not sensitive enough to use a low ABCD2 score to identify patients who can be sent home (would miss about 10% of early CVAs in this study).  However, it is definitely true that as the ABCD2 score goes up, the pt’s risk of CVA increases,  so calculating the ABCD2 score is useful to more accurately counsel high scoring patients about their risk of CVA, encourage lifestyle modification, and these patients should be relatively easy to admit after discussion with PMD.

2.  Rothwell PM et al. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison. Lancet. 2007;370:1432-1142.

In this prospective before-and-after English study of 1278 patients presenting with TIA or minor stroke, the authors compared their local  practice of having PMDs refer patients to a daily TIA clinic, which was appointment based, with no treatment immediately started (Phase I), to treatment at a TIA clinic where no appointments were necessary, and at which treated was immediately initiated if the diagnosis of TIA or small stroke was confirmed (Phase II).  All patients received neuroimaging and carotid US, some patients received Echo.  Patients were followed up for 24 months (100% followup), and the primary outcome was CVA within 90 days.  Risk of CVA at 90 days fell from 10.3% in Phase I to 2.1% in Phase 2 (huge).  Early treatment did not increase the risk of ICH or other bleeding.  Although this is an extremely positive study, it’s important to look at the access to care timing.  Median delay in assessment in the TIA study clinic fell from 3 days in Phase I to less than 1 day in Phase II.  Also, median delay to first prescription of treatment (ASA, clopidogrel, BP meds) fell from 20 days to 1 day.  So, it’s difficult to extrapolate this to the United States, where patients are seen/have a CT/and are started on ASA or other meds at the time of their presentation to the ED (not 20 days later).  Maybe some of the great outcomes in this study were because their Phase I was so slow.  The authors acknowledge that starting meds early likely was the largest factor in their positive results, although patients in Phase II requiring CEA received surgery earlier than in Phase I. 

Also, there is the possibility of the Hawthorne effect coming into play.  As an example, patients in Phase II were more likely to be on statins at the time of initial presentation than patients in Phase I, and it’s possible that other minor subtle changes in care were taking place during the second phase which influenced the overall outcomes of these patients and added to the positive results. 

Bottom line:  Early diagnosis and treatment of TIA is associated with improved clinical outcome, but it's unknown how much of their huge benefit was a reflection of the inefficiencies of their system at baseline.

3.  Ross MA et al. An Emergency Department Diagnostic Protocol for Patients With Transient Ischemic Attack: A Randomized Controlled Trial. Annals of Emergency Medicine. 2007;50:109-119.

Finally, this study examines the efficiency and potential cost savings of an ED Observation Unit based accelerated diagnostic protocol (ADP) for TIA.  The study randomized 149 patients with TIA either to an ADP which included cardiac monitoring, carotid dopplers, echo, neuro checks and a neuro consult, or to hospital admission.  The same order set was used for ADP patients and admitted patients (although some admitted patients never receive all of the tests).   Primary outcome was the index visit length of stay.  Secondary outcomes were 90 day cost, and 90 day clinical outcomes (which included CVA).  Ninety day followup occurred with all patients.  There were a large number of inclusion/exclusion criteria to be enrolled, resulting in many patients with TIA not being enrolled in the study.  However, when comparing the 2 groups, patients in the ADP had a significantly shorter length of stay than admitted patient (30 hours shorter-basically saved a day), and 90 day costs were $890 versus $1,547.  Approximately 85% of ADP patients were discharged.  Clinical outcomes were similar, with comparable rates of return visits, CVA, and major clinical events.  All ADP admissions were for clinical events detected on serial clinical exams; no admissions were primarily because of carotid stenosis, arrhythmia, or echo findings.  That being said, it’s accepted that echo/carotid US findings which lead to emergent interventions are unusual (eg only 3% echo findings of cardioembolic source of CVA/TIA in the absence of clinical suspicion of cardiac etiology-2009 AHA Stroke Guidelines), and this study only enrolled 174 relatively low risk patients.  Not really powered to find significant clinical outcomes differences.  If significant carotid stenosis is identified, early surgical intervention is associated with improved outcomes.  Carotid US and Echo were performed more frequently and more quickly in the ADP group-need a larger study to see if this would make a clinical outcome difference.

A couple of other philosophical points.  Assigning hospital resources to a TIA protocol and prioritizing these patients to receive rapid diagnostic evaluations and neurology consults may mean diversion of resources from other patients in the ED/hospital.  On the other hand, rapid throughput/discharge of ADP patients allows backfill of open beds upstairs with patients needing different/more specialized resources.  There is a potential for overuse of this protocol-enrolling such atypical patients that it becomes a “no-risk” rather than “low-risk” protocol.   Point made that there are fewer TIA presentations than chest pain presentations to the ED, so decent chance this wouldn’t be a problem.

Bottom line:  an ED accelerated diagnostic protocol appears to be feasible and when enrolling low risk patients saves a day of hospital admission and significant money, with similar clinical outcomes.

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.



Reversal of Warfarin

Our question was:  given a generally healthy asymptomatic patient on warfarin for afib who is sent to the ED because of an elevated INR of 8 but who has heme + brown stool and a Hgb of 11, what is the appropriate intervention (hold warfarin only, or also treat with vitamin k, and if so, at what dose/route)?  What are the risks of bleeding, and what are the thrombotic risks?

First, as a reminder, our patient has a CHADS score of 1.  This represents an annual stroke risk of 2.8% for patients with afib (see below), so warfarin treatment is reasonable.   Unfortunately, even in warfarin clinics, INRs are outside the therapeutic range one third to one half of the time.  It’s well accepted that bleeding risk increases with increasing INR, especially when INR >4.  What is our patient’s risk of bleeding?   

Garcia DA, Regan S, Crowther M, Hylek EM. The risk of hemorrhage among patients with warfarin-associated coagulopathy. J Am Coll Cardiol. Feb 21 2006; 47:804-808

evaluated a cohort of 979 patients with a first episode of INR >5.  During 30 day followup, 0.96% of patients with an INR >5<9 experienced major hemorrhage.  When the INR >/= to 9, the risk of bleeding increased to 9.5%.  Only 9% of patients in this study received vitamin k (mostly 2.5 mg or less).  So, a good place to start:  there’s about a 1% 30 day risk of major bleeding when your INR >5 <9.  There were no ICHs in this study.  In the Aiyagari background article on ICH/warfarin, a range of 0.3-0.6% per year risk of ICH while on warfarin is quoted, but as Harwood pointed out, the risk of ICH skyrockets in the elderly.

So, how should we protect our patient?  The meta-analysis,

Dezee KJ, et al. Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis. Arch Intern Med. Feb 27 2006; 166:391-397

evaluated all of the RCTs and prospective nonrandomized trials using vitamin K to treat patients without major hemorrhage with an INR >4 on oral anticoagulants, from 1985-2004.  Unfortunately, as they admit, the quality of studies available was fair to poor, leading to a concern of “garbage in, garbage out.”  There were a few limited conclusions.  Subcutaneous vitamin K is no better than placebo.  Just don’t use it (and this is also part of the 2008 ACCP guidelines).  Oral and IV vitamin K worked about equally as well in this meta-analysis, but with the risks of anaphylactoid reactions with IV vitamin K, you should choose oral if the patient isn’t having major bleeding.  Most (about 80%) patients with INR <10 who receive oral vitamin K (2.5 mg or less) will have an INR < 4 in 24 hours.  That’s fine, but does giving vitamin K prevent bleeding?  Does giving vitamin K cause an increased risk of thrombosis? Sorry, but no answers from this meta-analysis due to the fair/poor quality of the included studies.

So, our third article came out in 2009.  It’s a large study of over 700 non-bleeding patients with INRs of 4.5 to 10, trying to look whether or not giving low dose vitamin K (1.25 mg) decreases bleeding risk.

Crowther MA, et al. Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: a randomized trial. Ann Intern Med. Mar 3 2009; 150:293-300  

At 90 days, this study demonstrated no significant difference in the rates of bleeding between patients receiving 1.25 mg vitamin K vs. those receiving placebo.  The study was under-powered to detect a difference in major bleeds, although interestingly, more major bleeds occurred in the vitamin K group (likely chance, but the major bleeds all happened >30 days out-could there be issues with re-starting warfarin and maintaining a therapeutic INR after receiving vitamin K?).  Although death and thromboembolism were rare and rates were balanced between the 2 groups, these were secondary outcomes and no firm conclusions are possible.  Erik Kulstad made several important points about the methodology:  there are issues of external validity (ability to apply study conclusions to your own patients):  patients enrolled in studies are different-they are compliant, in general healthier, and in this case had amazing followup with multiple phone calls, likely identifying problems/bleeding more frequently than in an unselected population.  Also, we are missing an explanation of who and how many patients were not included in the study-who are the ineligible and missed patients?

So, coming back to our patient….after much discussion, we took votes on 2 different patients:  first, our PICO patient, but without heme positive stools.  Everyone in the room agreed to send him home, and all except one would not give him vitamin K.  When the patient had heme + stools (occult GI bleed, no melena, and stable/asymptomatic), still most would send him home, although now many would given low dose vitamin K (1-2.5 mg, orally).  Again, as Harwood pointed out, you only need to change one variable to dramatically change risk and outcome and disposition (old, or melena, or poor social situation, or INR 11).  Still, we do see a ton of patients like our PICO guy, and I believe this JC supports being more comfortable with doing less than many us (me included) may have done in the past.  Interestingly, in the most recent ACCP guidelines from 2008, although the table looks similar to 2004, the doses of vitamin K recommended are half of the 2004 recs for patients without significant bleeding (both INR 5-9, and INR >9). 

Last point:  we chose the PICO patient deliberately:  the heme + stools and hgb 11 means that he isn’t really exactly  like any of the patients in our studies.  There is no “right answer” on how to treat him. Involving the patient in his medical decisions is the “third circle” of EBM (evidence, clinical experience, and patient values).  Maybe he is really afraid of a thrombotic stroke or MI.  Maybe he doesn’t have insurance and isn’t going to get his INR rechecked tomorrow.  You get the idea.

CHADS score for background:

	Condition	Points
C	Congestive heart failure	1
H	Hypertension (or treated hypertension)	1
A	Age >75 years	1
D	Diabetes	1
S2	Prior Stroke or TIA	2

Annual Stroke Risk

CHADS2 Score	Stroke Risk %	95% CI
0	1.9	1.2–3.0
1	2.8	2.0–3.8
2	4.0	3.1–5.1
3	5.9	4.6–7.3
4	8.5	6.3–11.1
5	12.5	8.2–17.5
6	18.2	10.5–27.4



Meta-analysis

Using meta-analyses to analyze the medical literature

EBM teaching point for the evening concerned meta-analyses. A well
performed meta-analysis (MA) is thought by many (but not all) to be a the top
of the evidence pyramid, stronger even than a RCT. Poorly done MA evoke the
phrase “garbage in-garbage out” and are basically useless. What makes a good
MA? It’s important for it to ask a specific question, to include an exhaustive search
of the literature for all appropriate articles, and to rank and include only high-
quality, consistent (low heterogeneity) studies. Why do a MA? A well done analysis
of a large number of individual studies or of individual patient data can combine
many small under-powered studies and come up with a clinically and statistically
significant conclusion. It can contribute to the generalisability of study results,
and generate new research questions, especially with regards to subgroups in the
studies.


1) Colman I, et al: Parenteral dexamethasone for acute severe migraine headache:
meta-analysis of randomised controlled trials for preventing recurrence.BMJ
2008;336:1359-1361.

This meta-analysis was felt by folks in the room to be easy to read, relatively easy to
understand, and met the “gut-check” of meta-analyses: when you look at the Forest
plot, which is the visual representation of the comparison of the treatment effects
of the different papers, you get a sense that although almost all the studies were too
small to show a statistically significant treatment effect, they all trended in the same
direction (favoring steroids), and when examined together in a MA, did achieve
signficance, with a NNT of 9 to prevent the recurrence of migraine within 72
hours. Side effects between treatment/control groups were similar. This illustrates
the power of MA; most of the original studies produced false negative results (type
II error) because they were small, but together, they have power to demonstrate a
treatment difference. Doses used were between 10-24 mg of dexamethasone,
with doses >15 mg showing a non-sig. increased treatment effect. It was pointed
out that for both this and the third study, one of the authors of the MA was also an
author of one of the original papers. Does that bias the MA? Does he have an ax to
grind to prove his point, or is he simply acting in the spirit of scientific inquiry to
find the true answer? You be the judge.

2) Patrick S, et al: Supraclavicular Subclavian Vein Catherization: The Forgotten Central
Line. West J Emerg Med 2009;10:110-114.

This article is not a MA, but a review of some literature on the supraclavicular
approach to the subclavian central line. As such, although it includes information
about some different studies on this approach, it’s conclusions are much more “we
like it” rather than a definitive evaluation of the approach’s merits and potential
complications. That being said, everyone in the room (except Jaime and Drew
S.) seems to like this line a lot. It’s landmark based, avoids the chest during CPR,
and makes great intuitive anatomic sense. It’s non-compressible, so not for
coagulopathic patients, and to use US, you would need a small footprint (“pencil”)
probe. Complication rates seem no higher than other neck lines. There are
multiple variations, but the original and most popular seems to be the Yoffa
approach (just lateral to lateral belly of SCM, 1 cm posterior to clavicle, direct
at 45 degrees to sagittal and transverse planes, and 15 degrees below coronal
plane-great diagrams in Roberts/Hedges or online). So try it, you’ll like it!
Residents, an appeal to all of you to push your comfort zones and try all approaches
to these lines, both with and without US.


3) Annane D, et aL: Corticosteroids in the Treatment of Severe Sepsis and Septic Shock in
Adults: A Systematic Review. JAMA 2009;301(22):2362-2375.
Finally, the bruiser of the group. Unlike article #1, this MA is difficult to read,
complicated, and the conclusions are not intuitively obvious when looking at its
Forest plot. In the conclusion, the authors suggest that low-dose, prolonged
course steroids be given, although only to adults with vasopressor-dependent
septic shock (although the MA evaluated/drew their conclusions from studies
including patients with both severe sepsis and septic shock). It’s important to
remember that overall, this MA showed no sig. effect of steroids on 28 day mortality,
and only by carving out the prolonged course/low dose trials did they come up
with a significant reduction in 28 day mortality. This brings up the issue of sub-
group analysis, and whether there is ever a time when a subgroup analysis, even
derived a priori, showing a large treatment effect, and making intuitive sense, can
be used to support a conclusion in a study. Short answer: sub-group analyses
should only be used as hypothesis generators for future studies. Multiple sub-
group analyses open up the risk of a Type I error (false positive results-finding a
difference when one doesn’t actually exist). So, what do you do about steroids and
sepsis? As Chintan pointed out, in 2004 according to the Surviving Sepsis Campaign,
the answer to the question of “steroids in sepsis?” was Yes! , largely because of a
2002 study by Annane in JAMA. Then, Sprung et al published CORTICUS in NEJM,
which failed to demonstrate any mortality benefit with steroids. So in 2008 the
answer was No! Now, with this MA, the answer is ??? The informal consensus
from JC was support to giving steroids to patients with vasopressor dependent
septic shock who aren’t responding well to EGDT. That being said, there will
be significant practice variation, and this is yet another area of clinical uncertainty
in medicine. The philosophical point of the evening, brought home by E. Kulstad,
was that this uncertainty is common, and if embraced, can lead to shared decision
making, open doors for future study. There are currently 10 studies on low dose
steroids in sepsis in the pipeline.

CTA for low risk chest pain

Use of coronary CT Angiography in the evaluation of low-risk CP 

For starters, important to remember that the discussion is restricted to low-risk CP patients (our typical CPEP).  Tests will always have different performance characteristics in different patient populations.  Also, as discussed by CK,  our goal was to emphasize the prognostic/clinical strength of the test (how will these patients do once they are discharged from the ED?, can we pick up the 3-5% “missed ACS” cases?) rather than simply the diagnostic efficacy of the test (do the number of 50% blocked lesions match the number of lesions seen on invasive angiography?).   This is important, as EK mentioned in passing, because there is a whole other discussion out there about whether or not lesions seen on invasive angiography should be stented.   The COURAGE trial (April 12, 2007 NEJM) took patients with “stable” CP and documented 70% blockages on angiography or abnormal stress tests, and showed that mortality/MI rates were the same with maximal medical management or stenting.  So, our articles:

1.    Goldstein J, et al:  A Randomized Controlled Trial of Multi-Slice Coronary Computed Tomography for Evaluation   of Acute Chest Pain.  JACC 2007; 49(8):863-8712.     

197 low-risk patients, really compared 2 protocols; either 0/4 hour ECG/CIP then CTA, or 0/4/8 hour ECG/CIP then nuclear med (SPECT) stress testing.   No test complications in the CT group, and no major adverse cardiac events at 6 months in any of the patients sent home from either group.  Ultimately, accuracy was  equivalent for the two approaches.  Twenty-four % of the CTA group had intermediate disease on CTA or nondiagnostic CTA; these patients all required a second test (SPECT).  There were also 11% false positive CTAs.   The article emphasized the shorter ED length of stay for the CTA patients, but this was largely because of the additional time built into the SPECT protocol (a shorter rule-out time would have cut out much of the difference), and there was a several hundred dollar difference in “cost of care”, and as SA and CM pointed out, “cost of care” determinations are pretty much hand-waving.  Also, only a 4% rate of disease in the whole group- in this small study of only 200 patients, safety conclusions will have wide confidence intervals.

2.  Hollander J et al:  Coronary Computed Tomographic Angiography for Rapid Discharge of Low-Risk Patients With Potential Acute Coronary Syndromes.  Annals of Emergency Medicine, In Press.  

568 patients evaluated with coronary CTA, low TIMI score, either receiving CTA without serial CIP (some received one set) or CTA after observation period (if they came to the ED at night).  Everybody did great (except for the guy who died in a car crash).  No major adverse cardiac events at 30 days (0%, 95% CI 0% to 0.8%).   Again, a very low risk population (6 patients out of 568 received stents).   Conclusion that CTA can be used to safely send home low risk patients (<1% risk of MI/death at 30 days).   One large issue with the study-patients were enrolled in part because emergency physicians had decided to order a coronary CTA on them, introducing a significant selection bias.

 3. Takakuwa K,  Halpern E:  Evaluation of a “Triple Rule-Out” Coronary CT Angiography Protocol:  Use of 64-Section CT in Low-to-Moderate Risk ED Patients Suspected of Having Acute Coronary Syndrome.  Radiology 2008;248(2):438-446. 

This study had the same primary outcome of adverse clinical outcomes at 30 days, 197 low risk patients, but used the “Triple Rule-out” protocol, which involves higher radiation but evaluates the rest of the thorax.  Negative predictive value for CTA 99.4%, but small study, low risk population, so CI 96.9%-100%.  They did find other stuff;  PEs, dissections, pancreatic and pulmonary masses, among others.  Unfortunately, no clinically information was reported about the patients, so impossible to say if clinicians were already worried about these other diseases or not (serendipitous finds vs. clinically suspected).  AN made the excellent point that in his case, a MRI (like a CT would have) diagnosed his constrictive pericarditis and gave him a new lease on life.  As a counterpoint, CK related how a CT with a ?tumor finding led to her unnecessary surgery.   Always a balance.


Other things to remember about coronary CTA:  

-Static rather than Functional (stress test) study.

-For now, you need to be in normal sinus rhythm, and usually need betablockers/NTG to slow the HR and max. open the vessels to get good pictures.  Stents and high calcium scores muck up the pictures.
  
-Think about the potential complications/patient exclusions.  The radiation dose is substantial (10-20 mSv), which is estimated to increased overall cancer risk by 1 in 200 to 1 in several thousand.  Doesn’t mean not to do it, but easily ordered technologies tend to be overused-just something to think about.  Along the same line, what happens when the patient returns the next year with similar pain?  Another CT and more radiation?  How long are they “good for”?  Unknown.

-In these studies, no renal issues from the dye load, but they (and all studies so far) have been small-no more than several hundred patients.

Can I wrap it up already?  The room was pretty evenly split at the end of the night on whether they would advocate for this test in the vignette patient.  I think the potential speed of the test (at least compared to our current CPEP) was appealing to some.  To others, the potential to find other disease/explanations for the pain is an important selling point (“triple rule-out).  Remember, in these low risk patients, there is such a small chance of a poor outcome that you could just send them all home without any testing and be right 90-95% of the time, so we really need much larger studies in this low risk group to be happy about safety  (CIs for adverse cardiac outcomes are just too wide in studies 1 and 3.   Study 2 with <1% risk of adverse event at 30 days but significant selection bias).  For now, based on available data, coronary CTA is probably safe in low risk CP patients (similar performance to stress echo or nuclear stress/SPECT), and if you are trying to get more “bang for your buck” (thinking cardiac vs. PE, or cardiac vs. dissection), this might be the way to go.   SA also brought up the excellent point that depending on where you practice, if it’s a small hospital, this test can be tele-radiologied to someone to read even if you don’t have a CTA radiologist on-site, and you might not have a cardiologist available to do stress echoes.   So it comes down to patient selection (is CTA safe for your patient, and how clear is their clinical presentation) and what are the available resources/alternative strategies at your institution. 

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.  


Thrombotic headache

Mythbusting!!!

It’s time we start to take a closer look at commonly held misconceptions and rules perceived as law!

1. Seafood allergy = iodine allergy = contrast allergy

1. A seafood allergy is to the tropomyosin protein (more concentrated in shellfish and crustaceans), not iodine concentration
2. Contrast allergy is a misnomer, it’s an idiosyncratic (unpredicatable, non-IgE mediated) reaction which is anaphylactoid and has, to date, resulted in no deaths

1. Schabelman & Witting. The Relationship of Radiocontrast, Iodine, and Seafood Allergies: A Medical Myth Exposed. The Journal of Emergency Medicine, 2010 39:5 701-707

1. Insurance companies do not pay for AMA

1. THEY DO!  Don’t use this as a scare tactic because it is false
2. Widger, et al (doi:10.1016/j.annemergmed.2009.11.024) did a chart review to bust this one

1. Ketamine cannot be used in head injured patients

1. Early studies proposed this myth in the 1940s and were on un-intubated patients who likely had respiratory depression, resultant increased pCO2 inducing increased ICP
2. Some studies currently posit a neuroprotective effect of ketamine!

1. CJEM 2010;12(2):154-157

1. Anesthetic with epinephrine causes ischemic necrosis in areas of non-dual blood flow

1. Tissue ischemia takes hours to set in, and is irreversible at 6-12h (think of torsed testicles, ovaries, amputated appendages, etc)
2. The half-life of epi is considerably shorter than this time period

1. Droperidol should not be used because of it’s high incidence of QT prolongation and severe side effect profile and blackbox warning!

1. Insapsine (droperidol) is a cousin of haldol and highly effective in treating acute agitation states, nausea, and psychosis
2. To date, no study has shown a direct causal relationship between the reported QTp and droperidol
3. More concerning, all claims of this effect were reported to the FDA within 48h of each other and none were reported thereafter!

1. Dig-toxic patients CANNOT receive calcium!!!

1. 161 patients with digoxin toxicity in one hospital over 17.5 years, 23 received calcium, and no one developed stone heart, whatever the hell that is!
2. Dig-toxic pt w/ hyperkalemia NEEDS calcium!!!

1. Levine M, Nikkanen H, Pallin D. The effects of intravenous calcium in patients with digoxin toxicity. Journal of Emergency Medicine. 2011; 40(1):41-46

1. Magnesium levels are accurate predictors of true cellular concentrations

1. Mag is an intracellular ion, therefore serum concentrations have no bearing on intracellular levels and cannot be used to predict total body volume
2. When in doubt, just give some Mag, it helps for SO MANY things!

1. Creatinine and GFR are real-time indicators of renal function

1. Creatinine is similar to Hb, it represents renal function 10-12h ago, and most GFR is simply an estimated calculation from Cr and does NOT accurately correlate with real-time renal function  

1. Flat or Trendelenburg positioning with a shoulder bump correctly positions a patient for direct laryngoscopy

1. Actually, a patient in the semi-Fowlers position (sitting up at about 20 degrees) with their head tilted (external auditory meatus in line with sternal notch) correctly approximates an optimal viewing angle

1.  aVR is a useless lead and should not be interpreted

1. STE in aVR has high specificity for proximal LAD occlusion >85%

1.  S1Q3T3 is pathognomonic for acute PE

1. Sens/spec of this finding for APE are extremely poor

1. Prog Cardiovasc Dis 1975 Jan-Feb;17(4):247-257)

1. Negative T waves in leads III and V1 allows APE to be differentiated simply but accurately from ACS in patients with negative T waves in the precordial leads

1. Am J Cardiol 2007;99:817– 821

1. Consider PE if 3 of following:  RBBB especially with ST elevation or T inversion in V1, prominent S waves in I or AVL, shift of transition zone to V5, Q waves in III or aVF, RAD or indeterminate axis, low QRS voltage in the limb leads, T wave in inversions in III, aVF or V1-4. 

1. Sreerama, et al. Am J Cardio 1999, 4:73

1. The most sensitive signs were tachycardia and incomplete RBBB (late R wave in aVR.  S1Q3T3 was equally present in those with and without PE 

1. AM J Cardiology 86:2000

1.  PO/IV contrast increase diagnostic accuracy of appendicitis, diverticulitis, etc.

1. Unenhanced vs enhanced CT sensitivity for appendicitis was similar (95% vs. 92%) as was specificity (97% vs. 94%) and accuracy (97% vs. 89%)
2. Numbers are about the same for diverticulitis

1.  Ultrasound has no role in the evaluation of adults with a concern for appendicitis because it is insensitive

1. Formal US: sens 89-98.5%, spec 95-99%, PPV 86-98%, NPV 96-98% (Dilley, et al; Baldisserotto et al)
2. When surgeons performed both the US and the clinical examination, they attained a sensitivity of 98
3. 2x the incidence of perforation found at time of CT as compared with US

1. Avg time of appy dx w/ CT is 7.9hrs vs US at 64min

1.  Blood at the urethral meatus is an absolute contraindication to Foley catheter placement

1. This came from an opinion piece by a Urology professor in 1955 and has lived on as dogma ever since, never to be corroborated with facts…
2. Treatment for a urethral tear is a Foley, urethral tear or dislocation seldom presents with blood at the meatus, forceful Foley placement is more likely to cause urethral damage than gentle placement in the face of known urethral injury!
3. You can attempt gentle placement once before obtaining imaging (J Trauma 2007;62(2):330)

Hives

A common presenting complaint, do not simply pass off these individuals as a hypersensitivity reaction or benign condition without ruling out the multiple causes of hives precipitation.  It’s best to isolate them into 5 broad categories…

Infectious	Environmental	Physical	Malignant	Autoimmune
Pharyngitis	Heat/cold exposure	Pregnancy (PUPPP)	Lymphoma	Rheumatoid arthritis
URI/GI/GU infx	Food allergies	Stress	Leukemia	SLE
Fungal/parasitic infx	Dust, molds, pollens, danders	Exercise	Other carcinoma	Polymyositis
Virus (coxsackie, hepatitis, EBV, etc)	Sulfites, tartrazine, benzoates			Vasculitides
Mycoplasma	Water exposure			Amyloidosis
Syphillis	Sun exposure			Sarcoidosis
Malaria				Hyperthyroid

• Workup
  • Physical exam
    • HEENT: pharyngitis? thyroid dz? Lymphadenopathy
    • CV/Resp: URI? axial lymph nodes
    • Abd: Signs of liver dz?
    • Skin: Signs of autoimmune dz, check feet for fungemia
  • Definition of a “Hive”
    • Well-circumscribed, raised, blanching lesion w/ erythematous borders and central pallor
    • Linear, circular, or serpiginous; tend to be migratory and transient
• Labs
  • If acute, not needed
  • If chronic (>1wk), consider CBC, CMP, ESR, CRP, CXR
    • Eosinophilia? Leukocytosis? LFT elevation? Inflammation?
• Treatment

1. Antihistamines
   1. First-line, should be initial treatment of choice
      1. Hydroxyzine, Benadryl, brompheniramine, loratadine, fexofenadine, certrazine
   2. For cold urticaria, cyproheptadine (2-4mg bit/tid) might be best
   3. For cholinergic urticaria (exercise/stress/heat) , hydroxyzine might be best
2. Steroids
   1. Second-line, employ only if antihistamines fail

Eclampsia

1. These are rare but truly emergent conditions of both pre- and post-partum women, with documented cases of both found up to 6 weeks postpartum!

1. Pregnant pt >20wks is pre-eclamptic if…

1. +HTN (>140/90)
2. Proteinuria (>300mg/24h)

1. You won’t diagnose this in the ED, but a dip w/ large protein is indicative

1. If <20wks with HTN and proteinuria likely has a molar pregnancy
2. 16% of pts w/ eclampsia may not have HTN, 38% might not have proteinuria!

1. Mattar, F, Sibai BM. Eclampsia. VIII. Risk Factors for maternal morbidity. Am J Ob Gyn. 1990;163:1049-55.
2. Douglas KA, Redman CW. Eclampsia in the United Kingdom. BMJ. Nov 26 1994;309(6966):1395-400

1. Pre-eclampsia + seizure = eclampsia

1. Seizure not secondary to…

1. Pre-existing epilepsy, electrolyte disturbances, intracranial pathology, trauma

About the Seizure

1. 80% of seizures occur intrapartum or w/in 48h postpartum
2. Seizure is classically tonic-clonic and triphasic…

1. Phase 1:  15-20sec, begins w/ facial twitching, body becomes rigid, leading to generalized muscular contractions
2. Phase 2:  ~60 sec, starting in the jaw, moves to the muscles of the face and eyelids, and then spreads throughout the body

1. Typically there is a cessation of breathing during this phase

1. Phase 3:  Coma or post-ictal state with hopeful recovery to confused or normal state, but patient will have no recollection of even

1. May have hyperventilation to compensate for previous breath-holding

Pathogenesis

1. Eclamptic pts have insufficient uteroplacental arterial development and there is an imbalance in vascular growth factors
2. Endothelial dysfunction is prominent in the brain and kidneys and increased leptin levels increase oxidative stress and neutrophil invasion into blood vessels and subsequent destruction
3. Decreased cerebral blood flow due to HTN, along with increased vascular permeability subsequently leads to cerebral edema and encephalopathy

Clinical Features

1. Headache (80%, usually frontal)
2. Generalized edema (50%)
3. Visual disturbances (30-40%, usually photophobia or blurred vision)

WORKUP	DIFFERENTIAL
POC Tests:  dexi, pulse ox, udip	Adrenal insufficiency/crisis
	Intracranial pathology (stroke, tumor…)
Labs: CBC+smear, DIC panel (coags, fibrin split products, haptoglobin, LDH), CMP, lactate, protein/Cr ratio (urine) helps the floor	Sepsis
	Hypoglycemia
Imaging: CT Head (not routine, but 50% of women imaged show abnormalities)	Drugs/EtOH (or withdrawal)
Diagnostics: Continuous fetal monitoring	Metabolic derangement

Management:

1. IV, O2, monitor, advanced airway equipment to the bedside
2. Activate OB early (delivery is the only cure)
3. Move pt to left lateral decubitus position and pad gurney
4. Medications…

1. Sz first line:  Mag sulfate (load 6mg over 20min, then 2g/h gtt)

1. If seizing after initial bolus, additional 2g bolus can be given
2. Monitor DTRs for signs of toxicity and consider Ca if decreased
3. 85% of seizure activity responds to Mag alone

1. Sz second line:  BZDs or phenytoin
2. HTN: Hydralazine (5-10mg) or labetalol (20-40mg q15min prn)

1. Ensure sBP>90 (will cause placental insufficiency)

1. If <32wks gestation: betamethasone (12 mg IM q24h × 2 doses) or dexamethasone (6 mg IM q12h × 4 doses) for fetal lung development

17 y/o with chest pain

This guy developed chest pain about 1 week ago after playing basketball, felt SOB with exercise only. He saw his PMD on day of presentation who did outpt xrays. Below is his repeat ACMC CXR.

The reading is a complete left sided PTX, if the image isn't clear. So, how do you treat it? It's a simple PTX, not trauma. Does it require a chest tube, catheter aspiration, or even needle aspiration?

At the time, I thought it was too big for anything other than a chest tube. It had also enlarged from a few hours earlier (from about 70% to complete collapse), although the patient was stable (comfortable at rest, normal VS, and normal O2 sats). Looking it up afterwards, some teaching points.

1) Aspiration is successful in about 65-80% of simple PTX (no underlying lung disease, no trauma). The rate of PTX recurrence is the same as if a chest tube was placed.

2) If you put a catheter in the chest, it should be small (14 F or smaller). A chest tube should also be small (16 to 22 F).  You can put a Heimlich valve on the end if the lung seems to expand well, instead of suction.

3) For a small (<2 cm) PTX that isn't causing "breathlessness", don't do anything but monitor per British Thoracic Society.

4) BTS advocates needle aspiration for all simple PTX regardless of size. Most studies (few patients) had patients with small to moderate PTX. Either way, the patient will need 6 hrs obs in the ED and repeat CXR. Leaving a catheter in place so more air could be aspirated is a nice option.

5) Patients with underlying lung disease (eg COPD) probably won't do as well, but BTS advocates giving aspiration a shot.

What did I do? Put in a 20 F chest tube (with ketofol) to wall suction. His lung went to 95% inflated immediately. Maybe next time I'll try 14F catheter aspiration. see http://emedicine.medscape.com/article/1959416-overview#aw2aab6b4 for technique

New onset-seizure in a 9y/oF

Patient is a 9y/o F with a PMH of sickle cell disease who presented to the emergency department with new onset seizure. Parents thought patient had a tactile fever and cough at home over the past two days. At the OSH CBC demonstrated hgb of 6.3 (baseline 7.0), and with normal reticulocyte count base don disease.

On our exam here patient  had right sided weakness RUE > RLE, and "knew the words she wanted to say, but was unable to effectively communicate them" (what type of aphasia and where is the lesion?)

CTH was unrevealing and patient was transferred to our PICU.

MRI/MRA of the brain was completed that demonstrated:

MRI  brain  without  and  with  contrast:  Patchy  areas  of  restricted  diffusion  and

hyperintense  FLAIR  signal  throughout  several  portions  of  left  cerebral

hemisphere  primarily  at  the  left  middle  cerebral  artery  territory  (including

left  parietal  lobe  cortex  at  superior,  mid,  and  inferior  levels,  left  lentiform

nucleus,  left  internal  capsule  posterior  limb,  left  caudate  body/periventricular

region,  and  superior  left  frontal  lobe  cortex).  Increased  vascularity  of  left

cerebral  hemisphere  on  postcontrast  series  in  the  affected  regions  may  represent

luxury  reperfusion.

Treatement?

Exchange transfusion was begun with placement of a quinton catheter and a goal HgS < 40%, and a Hct > 21%.

Heparin-Induced Thrombocytopenia

62y/o F 12 days s/p CABG presents to the er with a swollen hand to GCB hall 2. Patinet says she went to bed last night and awoke this morning with severe hand numbness, a bluish hue, and edema. Per the patient it was "completley normal last night" She has a small back escar over the area where a radial A-Line cutdown was completed. patient has only the complaints of numbness in the hand, but has normal motor functions. 

PE: 36.6, 102, 12, 140/64, 99% on RA

HAND: patient has NO palpabale or dopplerable radial PULSE, she does have a triphasic ulnar pulse. her fingers are blue, and insensate at this point. her motor exam is unremarble. her entire left upper ext appears edematous as does her lower ext. 

Labs start rolling back in:

CBC: 8<11.1>18K   CBC (5days prior): 9<10.1>220K

Chart biposy shows that patient was on a heparin drip as an inpt which caused MASSIVE vaginal bleeding and required holding the heparin transfusion. She no longer was placed on heparin post-CABG, however HEPARIN is known to be in the flushes that nursing uses on a Central line.

So by now most people have the diagnsois of heparin-induced thrombocytopenia, but there are several important points about this case, because like STEMI's time is tissue and if you miss the diagnosis or just think that they can figure it out onthe floor the patient may loose their arm. 

1. There is an EXTREMELY high mortality rate in patients that develop HIT with thrombosis. This lady had a radial aa thrombus, b/l UE DVT's and 2 LE superficial vv thrombuses, and it's only time before she develops clots in places that cells cannot be regenerated (myocardium, brain parenchyma, lung). 

How do you diagnose this?

1. High index of suspicion in patients with thrombocytopenia even if they are NOT RECIEVING HEPARIN currently. This is an IgG mediated phenomenon, and it can be dalyed up to 5-14 days after last dose. 

4 T's of HIT

1. Thrombocytopenia: 2 pts if plt count fell >50% of previous value, 1 pt if 30-50%

2. Timing: 2pts if fall is betwn 5-10days after exposure, 1pt after day 10

3. Thrombosis: 2pts new thrombosis, skin necrosis, or systemic rxn. 1 pt if progressive or recurrent thrombosis

4. alTernative Cause: 2pts if no other cause, 1 if there is another possible, 0 if no definite other cause

0-3 Unlikely, 4-5 intermedia, 6-8 HIGHLY probable (our ladies score was 8). 

Why do they clot when they are thrombocytopenic?

The immune complex of the patients IgG ab's to the heparinoid complex(heparin and plt factor 4 DELETE FROM MEMORY PLEASE), bind to receptors on the plts, activating them and causing thrombosis which from blood clots and cause the platelet count to drop. Think of this like the ADAMS factor in TTP causing plts to aggregate. 

How do I treat this???

1. Agatroban drip is LIFE/LIMB-SAVING. Approximate RR 0.2, with relatively narrow CI. It sounds strange that an anti-coagulant would be life saving in a patient with thrombocytopenia, but think of this entitiy similar to TTP.

AVOID plt transfusion in these patients as well.

So how did our lady do?

-Saved her limb, she dveeloped color and flow to her hand, and regained some of her sensation in LUE. 

STATUS ASTHMATICUS

23y/o F presents form EMS with "SEVERE ASTHMA". Patient is hypoxic satting 78% on 15L NRB in the rig. Patient is obtunded on presentation diaphoretic and cyanotic. Her sats are in the low 80s on an ambubag at this point.

What would you do?

This patient weighs approximatel 260lbs, and is clearly in distress. She is barely moving air and is extremely tight. Here's what we did: 4g magnesium, ambubag with PEEP valve and 2LNC for increasing PEEP. 150mg of IV ketamine and 2mg of IV versed. Ventilator to the bedside and get her sats up. With the NC and ambu bag sats come up to 100%, color returns patient is clearly anxious fighting and agitated, rather than obtunded now. She will NOT tolerate bipap.

Decision is made for intubation but she is obese. RAMP positioning (thanks dr. g), head is elevated 30 degrees. Nasal cannula is left on DURING the intubation as patient is RAPIDLY desaturating when the BVM is taken off face (she has no cardiopulmonary reserve, due to her intrinsic lung disease and reduced FRC). Patient gets an awake look(this was right after ketamine and versed were given) to see what airway looks like and after cords are visualized patient begins to gag, decision to push paralytics is made. Patient intubated and initial vent settings are!?

AC 8/450/100%/0

We are now hearing air move patient is no longer auto-peeping, she is not hypoxic and her end-tidal is about 70 on waveform capnography (dont forget to change settings to see the graph suually only goes as high as 50).

But about 6 minutes after paralytics are pushed patient is getting agitated here rr increase to 18 and her sats come down. her PCO2 begins to drop and her peak pressures SKY ROCKET to the 80s, clearly she is under sedated.

An insp hold for plateau pressure is completed and a sickening SIGH and wheeeze is heard from the ET tube as the patient expires all the auto peep. Boluses of fentanyl and versed are given while we attempt to paralyze patient with nimbex in order to gain complete control of resp status. BUTTT we cant give nimbex in the er because nurses are NOT trained apparently in this. So instead a bolus of rocuronium was given to buy time with high doses of propofol were given for sedation (BP was very elevated from sympathetic response).

Initial ABG after propofol and a push of rocuronium is: 7.0/102/406/25, clearly a resp acidosis.

We decide bicarb drip is the way to go and allow her to increase rate to 10 with repeat gas of

7.1/96/87/29 on AC 8/450/50%/5

In the ICU managemnet is continued with train of fours for sedation on nimbex, and patient is given heliox 20/80. Patient doing well much improved day one in ICU.