Patient Satisfaction

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Ketofol

Ketamine/Propofol versus Single Agent for Procedural Sedation

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

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

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

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

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

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

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

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

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

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

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

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

 

SUMMARY:

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

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

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.



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.