Atrial Fibrillation, You’re a Heart Breaker, Dream Maker, Love Taker:

But At Least There is Low Risk for Thromboembolic Events With Speedy Conversion to Sinus Rhythm…

This post reviews the article from Weigner, Marilyn et al. “Risk for Clinical Thromboembolism Associated with Conversion to Sinus Rhythm in Patients with Atrial Fibrillation Lasting Less Than 48 Hours,” from the Annals of Internal Medicine in 1997 as part of the ongoing 52 article series.

Main Points:

  1. This article reveals only a 0.8% risk of clinical thromboembolic event for patients who were clinically estimated to be in atrial fibrillation for less than 48 hours.
  1. This trial data supports the recommendation for early cardioversion, either pharmacologic or through electric cardioversion, in patients with recent onset of symptoms without the need for prior diagnostic imaging to evaluate for clot burden.

Background:

Atrial fibrillation is a common arrhythmia and responsible for over 250,000 hospital admissions annually. Patients often feel the effects of depressed cardiac output from the loss of atrial systole and seek medical attention in hopes of improved quality of life. Patients may describe a range of symptoms including palpitations, dyspnea, dizziness, angina and fatigue. Studies have demonstrated that patients with atrial fibrillation for more than two days may have a greater than five percent risk of clinical thromboembolism and often require weeks of anticoagulation or screening with transesophageal echocardiography prior to cardioversion. This study sought to answer the question of whether or not patients who experienced only a short duration of symptoms were low risk for thromboembolic disease.

Details:

This was a prospective study of consecutive patients at two academic medical centers, Beth Israel Deaconess Medical Center in Boston, MA and the John Dempsey Hospital and University of Connecticut Health Center in Farmington, CT. 1822 adult patients with a diagnosis of atrial fibrillation were screened and 375 patients who were clinically estimated to have symptoms for less than 48 hours were enrolled. Those patients whose duration of symptoms were unclear or had already initiated long term anticoagulation with warfarin were excluded. Patients with a previous history of thromboembolic events were not excluded, but one patient who had an acute thromboembolism was not enrolled in the trial. Clinical and transthoracic echocardiography data and outcomes were collected from review of the medical records. Clinical embolic events were considered if they occurred during the index hospitalization or within one month after conversion to sinus rhythm. Conditions that may have predisposed patients to atrial fibrillation included: previous history of atrial fibrillation (181 patients, 48.3%), hypertension (156, 41.7%), coronary artery disease (114, 30.4%), infection (25, 6.7%), history of thromboembolism (23, 6.1%), excessive alcohol use (22, 5.9%), rheumatic heart disease (7, 1.9%). Patients were noted to have left atrial dimensions of 4.2 +/- 0.7cm (normal ≤ 4.0cm) and a left atrial length of 5.7 +/- 0.7cm (normal ≤ 5.2cm) based on transthoracic echocardiogram data. 218 out of 280 patients who had echocardiograms performed were noted to have at least some evidence of mitral valve regurgitation with 61 patients noted to have either moderate or severe regurgitation.

Patients converted back to a normal sinus rhythm either spontaneously or through pharmacologic or electric cardioversion methods. Conversion was considered spontaneous if it occurred without the use of medications or electricity or in the setting of use of ventricular rate-controlling agents (digoxin, beta-blockers, and calcium channel blockers).

Three patients (0.8%, 95% CI 0.2-2.4) were noted to have a clinically significant thromboembolism and surprisingly all converted spontaneously. The cases included a left parietal embolic stroked in an 86 year old female with history of hypertension; a right proximal brachial artery embolus in an 83 year old female with coronary artery disease; and a transient ischemic attack in an 89 year old female with a recent diagnosis of pneumonia.

This study was a consecutive series that relied on both real time data gathering as well as retrospective chart review.

Level of Evidence:

This study was graded a level II based on the ACEP Clinical Policy Grading Scheme for prognostic questions and had only minimal methodological flaws.

Surprises:

The three patients in this trial were identified as having increased risk for thromboembolism based of the Stroke Prevention and Atrial Fibrillation Study I and II, however, how best to achieve post conversion anticoagulation in the era of direct oral anticoagulants remains a hot topic for further study and debate.

Relevant articles:

Mookadam, M. Shamoun FE. Mookadam, F. “Novel Anticoagulants in Atrial Fibrillation: A Primer for the Primary Physician.” J Am Board Fam Med, 2015, 28(4):510-22

Source Articles:

Weigner, M. Caulfield, T. Danias, P. et al. “Risk for Clinical Thromboembolism Associated with Conversion to Sinus Rhythm in Patients with Atrial Fibrillation Lasting Less Than 48 Hours.” Annals of Internal Medicine, 1997, (126):615-20.

Faculty Reviewer: Dr. Siket

Spare the Tube, Save a Life

This is part of a recurring series examining landmark articles in Emergency Medicine, in the style of ALiEM’s 52 Articles.

Discussing:

Brochard, L. Mancebo, J. Wtsocki, M. et al. “Noninvasive Ventilation for Acute Exacerbations of Chronic Obstructive Pulmonary Disease.” NEJM 1995, 333(13):817-22.

Main Points:

  1. In this randomized prospective multicenter trial of 85 patients admitted to ICUs throughout Europe with COPD exacerbations, noninvasive ventilation reduced the need for endotracheal intubation, length of stay and in-hospital mortality rate.
  1. 31 of the 42 patients in the standard arm required intubation, compared to 11 of 43 patients in the noninvasive arm (p<0.001). These results were consistent among the five centers studied. The mortality rate and length of stay was similar in the two groups in whom endotracheal intubation was required, suggesting that the benefits observed in noninvasive ventilation resulted from lower rates of intubation.
Figure 1. Mask used to deliver noninvasive ventilation

Figure 1. Mask used to deliver noninvasive ventilation

Background:

COPD exacerbations often manifest as acute hypercapnic ventilatory failure and endotracheal intubation can be a life-saving procedure. This intervention, however, is not without associated risks both during the time of the procedure as well as later in the course of the patient’s care. This patient population is at risk for hemodynamic compromise during intubation and may be difficult to manage on the ventilator due to a multitude of concerns including air trapping and tachypnea. The risk for ventilator associated pneumonia and other complications secondary to being intubated for prolonged periods of time are also worth considering.

Brochard and his colleagues investigated the use of noninvasive ventilation in COPD exacerbations in hopes of reducing mortality through the reduction of intubation. Thiswas a multicenter prospective randomized study that recruited patients in five European ICUs. The primary and secondary outcomes were patient-centered and this article from 1995 has clearly framed the manner in which we manage the sick COPD patient today. The medications used and manner in which noninvasive ventilation is employed has evolved since the publication and a comprehensive review of management was published in 2010 by the American Academy of Family Physicians. ACEP also has published clinical guidelines on use of noninvasive ventilation in 2010.

Details:

This prospective multicenter study enrolled 85 out of 275 patients admitted to the ICU with COPD or a high probability of the disease based on careful history, physical examination and chest x-ray. Patients were selected if they had a respiratory acidosis and elevated bicarbonate level. Additional criteria included dyspnea for less than two weeks and at least two of the following: respiratory rate >30 BPM, partial pressure of arterial O2 <45 mm Hg, arterial pH <7.35 after the patient was breathing room air for at least 10 minutes. The exclusion criteria included: respiratory rate <12 BPM, need for immediate intubation-defined by strict criteria in the paper, already intubated, use of sedative drugs in the past 12 hours, CNS disorder, cardiac arrest in the past five days, cardiogenic pulmonary edema, neuromuscular or skeletal disorder, upper airway obstruction or asthma, clear cause of decompensation requiring treatment, or facial deformity. Patients were either assigned to the standard arm which included treatment with: maximum of 5LPM O2 by nasal prongs with goal O2 saturation >90%, medications such as subcutaneous heparin, antibiotic agents and bronchodilators (subcutaneous terbutaline, aerosolized or intravenous albuterol, corticosteroids or intravenous aminophylline), correction of electrolytes. The noninvasive arm received the same medications with the addition of periods of noninvasive ventilation. The same apparatus was used at all five sites to deliver pressure support of 20 cm H20 with an expiratory pressure that was atmospheric. Patients underwent noninvasive ventilation for at least six hours a day with overall duration determined by clinical criteria and arterial blood gal levels.

In order to standardize care, the authors created major and minor criteria as objective markers for the need to perform endotracheal intubation. The major criteria included: respiratory arrest, respiratory failure with LOC or gasping for air, psychomotor agitation making nursing care impossible and requiring sedation, HR<50 BPM with loss of alertness, hemodynamic instability with SBP <70 mm Hg. There was a series of minor criteria also relating to vital sign instability, mental status changes or arterial pH <7.3. In both groups the presence of one major criterion was an indication for intubation. After the first hour of treatment the presence of two minor criteria was an indication for intubation.

Patients were evaluated at the one hour, three hour and 12 hour mark following the initiation of therapy. The primary outcome examined was the need for endotracheal intubation with secondary end points including length of stay, complications not present on admission (pneumonia, barotrauma, gastrointestinal hemorrhage, renal insufficiency, neurologic events and pulmonary embolism), duration of ventilatory assistance, and mortality rate during hospitalization. 31 of the 42 patients in the standard arm required intubation, compared to 11 of 43 patients in the noninvasive arm (p<0.001). Per the authors, these results were consistent among the five centers studied, however, examining table 2 sites one and two seemed to have high percentages of intubation, 100 and 83 percent respectively, compared to the others. This may be skewed by the overall low numbers studied. Patients who ultimately were intubated both in the standard and noninvasive arms had extended ventilation time with 17 +/- 21 days and 25 +/- 17 days respectively. Complications and events leading to death are shown in Table 4.

Level of Evidence:

This study was graded a level I based on the ACEP Clinical Policy Grading Scheme for therapeutic questions.

Surprises:

The use of pressure support of 20/0 is quite different from the manner in which many providers initiate noninvasive ventilation today. This may be secondary to the limitations of the technology at the time because the photograph in figure 1 (see above) displays a mask that appears different from what you find on modern machines.

Relevant articles:

Ahn, J. Pillow, T. “Focus On: Noninvasive Positive Pressure Ventilation in the Emergency Department.” 2010, http://www.acep.org/Clinical—Practice-Management/Focus-On–Noninvasive-Positive-Pressure-Ventilation-In-the-Emergency-Department/

Evensen, A. “Management of COPD Exacerbation.” Am Fam Physician 2010, 81(5): 607-13. http://www.aafp.org/afp/2010/0301/p607.html

Faculty Reviewer: Dr. Siket

Source Articles:

Brochard, L. Mancebo, J. Wtsocki, M. et al. “Noninvasive Ventilation for Acute Exacerbations of Chronic Obstructive Pulmonary Disease.” NEJM 1995, 333(13):817-22.

Hold the Fluids: Rethinking Early Crystalloid Resuscitation in Penetrating Trauma

By: Dr. Maddie Boyle

This is part of a recurring series examining landmark articles in Emergency Medicine, in the style of ALiEM’s 52 Articles.

This blog post reviews the article by: Bickell WH, et al. Immediate Versus Delayed Fluid Resuscitation for Hypotensive Patients with Penetrating Torso Injuries. NEJM. 1994; 331 (17): 1105 – 1109.

Main Points:

  1. Early, large volume crystalloid resuscitation in the trauma patient with penetrating wounds and hypotension may lead to hydraulic disruption of a formed clot and a dilutional coagulopathy, thereby exacerbating hemorrhage and decreasing survival.
  1. Restricting isotonic fluids in the penetrating trauma patient with hypotension prior to operative intervention (where definitive hemorrhage control can be achieved) lead to higher survival rates when compared to those individuals treated with early, aggressive isotonic fluid resuscitation (70% vs 62%, p=0.04). This paper suggests a potential adverse effect from aggressive crystalloid administration and emphasizes the importance of prioritizing surgical management in the patient with hemorrhagic shock from penetrating trauma.

Background:

Historically, the standard approach for the trauma patient with hypotension has been aggressive volume resuscitation with crystalloid fluids in order to restore circulating volume and maintain organ perfusion. More recent studies suggest that aggressive crystalloid fluid administration prior to definitive hemorrhage control may be detrimental. Aggressive fluids in the bleeding patient may be deleterious for multiple reasons, most notably the risk of dislodging a softly form clot at the injury site with restoration of blood pressure and the risk of increased bleeding secondary to dilution of clotting factors when large volumes of crystalloid fluids are infused. Recent literature such as the PROPPR trial has investigated colloid based transfusion strategies, however, this study predates the data gathered from the recent Iraq and Afghanistan Wars.

The goal of this study was to evaluate fluid administration in hypotensive patients with penetrating torso trauma and determine whether delayed fluid-resuscitation (after operative intervention), compared to an early fluid administration conferred a survival benefit. Researchers performed a prospective, single center trial comparing immediate fluid resuscitation vs. delayed fluid resuscitation in patients with penetrating torso trauma with a pre-hospital systolic BP <90 mmHg requiring operative intervention for hemorrhage control. The study found a mortality benefit favoring delayed resuscitation: 70% of patients enrolled in the delayed-resuscitation group survived vs. 62% of patients in the immediate-resuscitation group (p=0.04). This study highlights numerous important questions regarding fluid strategy in the trauma patients, including the type of resuscitative fluid, the volume and timing of fluid administration. The results of this investigation continued to be queried today as research examines permissive hypotension and damage control resuscitation strategies in the trauma patient.

Strengths:

1: Adequate power.
2: Intention-to-treat analysis.

Criticisms:

1: Semi-randomized, non-blinded.
2: Generalizability: Study population was largely young, healthy adult males.
3: Feasibility: The average time elapsed from ambulance call to operative intervention was approximately 2-hours for each study group. This type of rapid response and expedited time to operative intervention may not be attainable by many hospitals.
4: External validity: study cannot be applied to patients with blunt trauma, traumatic brain injury (where fluid resuscitation to achieve blood pressure control is paramount) or in those penetrating trauma patients with delayed presentation.
5: No mention of neurologic outcome with regards to survival benefit.

Details:

Prospective, single-center trial.

Population: Adults or adolescents (age ≥16 years) with gunshot or stab wounds to the torso who had a SBP ≤ 90 mm Hg in the field, including those patients with no blood pressure at the time of initial paramedic evaluation.

Patients were separated into two treatment groups based on the day of the month. Patients injured on even-numbered days were assigned to the immediate-resuscitation group, whereas those injured on odd-numbered days were treated in the delayed-resuscitation group. Patients in the immediate-resuscitation group received isotonic crystalloid (ringer’s acetate) en route, and those with SBP <100 mm Hg upon arrival in the ED received continuous infusion of crystalloid or pRBCs when necessary as determined by standards established by the American College of Surgeons Committee on Trauma. The delayed-resuscitation group did not receive fluids, regardless of clinical condition, outside of those small infusions required to keep lines patent. Otherwise, the two treatment groups were treated identically in terms of pre-hospital and trauma care. The average time from emergency dispatch to surgical intervention was approximately 130 minutes in both groups.

Surgical interventions were dictated by the injury and included thoracotomy within the ED, thoracotomy in the OR, laparotomy, neck exploration, and groin exploration. During surgical intervention, IV crystalloid and pRBCs were given as needed, independent of study group assignment in order to maintain SBP of 100 mm Hg, hematocrit ≥ 25% and urinary output ≥ 50 cc/hr in both treatment groups. The total volume of crystalloid and colloid fluids provided in the OR was not statistically different between the two study arms, however, the rate of intraoperative fluid administration was noted to be 117 +/- 126 for the immediate resuscitation group and 91+/- 88 for the delayed resuscitation group with a p value of 0.008.

The primary outcome measure was survival, defined as patients who did not die during hospitalization. Secondary outcome measures included six prospectively identified post-operative complications including: sepsis, coagulopathy, acute renal failure, ARDS, pneumonia and wound infection.

598 patients were ultimately considered for the study. 309 were enrolled in the immediate-resuscitation group and 289 in the delayed-resuscitation group. The patients were similar in their baseline demographics and clinical condition. Of the 598 patients, 70 died before operative intervention. The remaining 528 had an operative intervention: 260 patients in the delayed-resuscitation group and 268 patients in the immediate-resuscitation group.

The mean fluid administration prior to operative intervention in the immediate-resuscitation group was 2611 ml. The mean fluid administration prior to operative intervention in the delayed-resuscitation group was 386 ml.

The overall rate of survival was higher in the delayed-resuscitation group vs. immediate-resuscitation (70% vs 62%, p-0.04). The immediate-resuscitation group trended towards more intraoperative fluid loss (p=0.11) and required a higher rate of intraoperative fluid delivery in order to maintain SBP >100 (117 cc/hr vs. 91 cc/hr, p=0.008). There was a trend towards more complications (ARDs, pneumonia, etc.) in the immediate-resuscitation group compared to the delayed-resuscitation group (p-0.08), however, no definitive explanation for why this may have occurred was discussed.

The authors of this study propose that their results suggest that aggressive fluid administration in the patient with penetrating trauma should be delayed until the time of operative intervention. They suggest a risk for greater bleeding, hemodilution and coagulopathy with aggressive fluid administration. The authors acknowledge the limitations of their study, most importantly its inapplicability to blunt trauma patients and patients with severe head injuries, but advise similar studies in these groups in the future.

Level of Evidence:

Class II utilizing the ACEP grading scheme for therapeutic questions

Relevant articles:

Timing and volume of fluid administration for patients with bleeding
Hypotensive resuscitation strategy reduces transfusion requirements and severe postoperative coagulopathy in trauma patients with hemorrhagic shock: preliminary results of a randomized controlled trial.
PROPPR trial

Source Article:

Bickell WH, et al. Immediate Versus Delayed Fluid Resuscitation for Hypotensive Patients with Penetrating Torso Injuries. NEJM 1994; 331 (17): 1105 – 1109.

 

Resident Reviewer: Dr. Anatoly Kazakin
Faculty Reviewer: Dr. Matt Siket

Ottawa Ankle Rules

This is part of a recurring series examining landmark articles in Emergency Medicine, in the style of ALiEM’s 52 Articles.

Discussing:  Stiell IG, et al. Decision Rules for the Use of Radiography in Acute Ankle Injuries. JAMA 1993; 269 (9): 1127 – 1132.

 X-Rays for ankle fractures? Is trouble a foot?

With a such a refined Canadian tool you can’t act like a fool.

 The Rules:

Ottawa Ankle

Main Points:

  1. The Ottawa ankle rule is an excellent screening tool for patients with ankle and foot injuries. In this study, it was found to have a sensitivity of 100 percent and is therefore unlikely to miss clinically significant ankle and midfoot injuries.
  2. These simple rules allowed physicians to safely reduce the number of radiographs ordered in patients with ankle and foot injuries by nearly a third.
  3. Based on the combined 1485 patients seen in the two stages the negative likelihood ratio for a fracture is estimated to be 0 for both the ankle and foot series rules!

Background:

Acute ankle injuries are one of the most common presenting complaints seen in the Emergency Department. Ankle radiographs are typically the second most commonly performed musculoskeletal examination, after the cervical spine. It was estimated that more than 5 million ankle radiographs are ordered annually in Canada and the USA with a cost of $500 creating a massive burden on the healthcare systems. Out of all of these images, treatable fractures are present in less than 15 percent of cases.

In 1992, Ian Stiell and his colleagues derived a clinical decision tool for the use of radiography in acute ankle and foot injuries. In the original study, thirty-two clinical variables were assessed for association with fractures seen on x-ray. Using these results, a set of rules were derived to determine if imaging was necessary for patients with ankle and foot injuries who met certain criteria. The goal of the study being reviewed here was to prospectively validate and potentially refine the decision rules to have the highest sensitivity possible, 100 percent, for identifying malleoli and midfoot fractures.

Methods:

The study was set up as a convenience survey and was prospectively administered in two stages: validation and refinement of the original rules, followed by validation of the refined rules in a new group of patients. For the study, injuries were subdivided into malleolar and midfoot zones. Patients who presented to the emergency department with pain or tenderness secondary to blunt ankle trauma due to any mechanism of injury were included. Patients were excluded if they were less than 18 years old, pregnant, has isolated skin injuries, were referred from outside facility with X-rays already completed, if injuries occurred more than 10 days ago, or if the patient had returned for reassessment of the injury.

Participants were evaluated by emergency medicine physicians who recorded their findings and interpretation of the decision rules on a standardized data collection sheet. All patients were then referred for radiography. Images were interpreted by radiologists who were blinded to the findings of the physician in the ED. Clinically significant fractures were defined as bone fragments greater than 3 mm in breadth, as avulsion fractures of 3 mm or less are not treated with plaster immobilization in the institutions involved in the study.

Data collected from the first stage was analyzed in order to refine the decision rules towards the objective of a sensitivity of 1.0. Each of the clinical variables were assessed for association with significant fractures in the ankle and foot radiographs. In the second stage, the sensitivity and specificity of the refined decision rules (see image above) was calculated and the accuracy and reliability of the physicians’ interpretation of the rules was determined. Continue reading

Time to Abandon Epinephrine for OHCA?

This is part of a recurring series examining landmark articles in Emergency Medicine, in the style of ALiEM’s 52 Articles.

Discussing: Wenzel, K. et al. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med 2004;350(2):105-113.

Main Points:

  1. For out-of-hospital cardiac arrest (OHCA), vasopressin was similar to epinephrine in patients with ventricular fibrillation or pulseless electrical activity, with regards to survival to hospital admission and survival to hospital discharge. Vasopressin was noted to be superior, in both outcomes, for patients with asystole.
  1. In patients with refractory cardiac arrest and no ROSC, vasopressin followed by epinephrine may be more effective than epinephrine alone.

Background:

With more than 600,000 sudden death in North America and Europe annually, optimization of CPR is crucial to improve a patient’s chance of survival. Epinephrine use has become controversial as it induces increased myocardial consumption and ventricular arrhythmias post-resuscitation. Endogenous vasopressin levels have been known to be elevated in successfully resuscitated patients. In small prior studies, vasopressin has been associated with higher rate of short term survival and improved blood flow to vital organs when compared to epinephrine. Current guidelines recommend the use of epinephrine during cardiac resuscitation, with vasopressin as a secondary alternative.

Details:

This study was a double-blind, prospective randomized clinical trial, conducted in 44 Emergency Medical Service units in three European countries, including those with OHCA unresponsive to defibrillation. 1186/1219 patients with OHCA were included in the trial with randomization to two injections of either 40 IU of vasopressin or 1 mg epinephrine, followed by additional treatment with epinephrine at the discretion of the emergency physician managing the resuscitation. Average age 66 years, 70% men, 61% attributed to cardiac causes, 78% arrests witnessed. 33 patients were excluded due to a missing study drug code. The rates of hospital admission were similar between the two treatment groups for patients with ventricular fibrillation (46.2 vs 43%, p=0.48) and pulseless electrical activity (33.7 vs 30.5%, p=0.65). Patients with asystole treated with vasopressin were more likely to survive to hospital admission (29.0 vs 20.3%, p=0.02) and hospital discharge (4.7 vs 1.5%, p=0.04). Among 732 patients without ROSC, additional treatment with epinephrine resulted in improvement in rates of survival to hospital admission (25.7 vs 16.4%, p=0.002) and discharge (6.2 vs 1.7%, p=0.002) in the vasopressin group, but not the epinephrine group. Continue reading

Hit Them Hard: The Use of H1 and H2 Antagonists for Acute Allergic Symptoms

This is part of a recurring series examining landmark articles in Emergency Medicine, in the style of ALiEM’s 52 Articles.

This blog post reviews the article by Lin, R. Curry, A. Pesola, G. et al. “Improved Outcomes in Patients With Acute Allergic Syndromes Who Are Treated With Combined H1 and H2 Antagonists.” Annals of Emergency Medicine, November 2000; 36(5):462-8.

Main Points:

  1. In this randomized, double blinded, placebo controlled trial of 91 patients presenting with acute allergic symptoms fewer patients in the active arm (ranitidine + diphenhydramine) had signs of cutaneous involvement such as urticaria at 2 hours compared to the placebo group (placebo + diphenhydramine).
  1. There was no significant difference, however, between the placebo group and active group with regards to the absence of erythema or angioedema at two hours.

Background:

Many patients present to the emergency department with acute allergic syndromes. Anti-histamines, primarily diphenhydramine, are the mainstay therapy in most mild cases and are both safe and cost effective. The addition of H2 antagonists such as ranitidine to diphenhydramine may help improve clinical outcomes and expedite management in the emergency department. The primary goals of this study were to look for resolution of urticaria and angioedema at two hours from presentation. This study was well balanced in its patient recruitment and overall provides insight into real-world application of a second agent for management of allergic symptoms.

Details:

The methodology within this study was rigorous, though the sample size was small. This trial was a randomized, double blinded, placebo controlled trial that enrolled 91 patients at an academic emergency department in New York, NY. Enrollment was based on a convenience sampling associated with the study physicians’ scheduling. Patients were enrolled in this study if they were adults who presented with acute urticaria, acute angioedema, acute unexplained stridor or acute pruritic rash following an exposure to a food, drug or contact with latex. Patients underwent vital sign monitoring, examination for physical findings such as: presence and extent of urticaria and erythema, presence of angioedema, wheezing, stridor, abdominal distention or tenderness, as well as symptom scoring. This data collection occurred at presentation, at 1 hour and 2 hours.

This study demonstrated a statistically significant difference, p=0.03, in the resolution of urticaria in the active group compared to the placebo group at two hours. One significant limitation in this study is that the treating physician was able to administer supplemental medications such as epinephrine, corticosteroids, bronchodilators and additional doses of antihistamine at their discretion with significantly more participants in the ranitidine arm receiving epinephrine, 17, compared to 9 in the placebo arm. The placebo arm had more use of additional antihistamine, 10, compared to 2 in the ranitidine arm. These additional therapies are documented in table 3; however, it is unclear if the severity of illness was equal between the two groups. The authors do note in their discussion that there was no observed covariate effect for epinephrine administration with respect to urticaria resolution.

Level of Evidence:

This study was graded a level I based on the ACEP Clinical Policy Grading Scheme

Surprises:

Within the sample groups there was significant history of asthma as well as other nonasthmatic atopic conditions which supports the theory that certain individuals are genetically predisposed to allergic syndromes.

Source Articles:

Lin, R. Curry, A. Pesola, G. et al. “Improved Outcomes in Patients With Acute Allergic Syndromes Who Are Treated With Combined H1 and H2 Antagonists.” Annals of Emergency Medicine, November 2000; 36(5):462-8.

Faculty Reviewer: Dr. Siket

52 Articles: Lysis vs Transfer for PCI (NEJM 2003)

ST segments:
fear
a lytic in my hand,
or transfer?

-Unknown, 2015

This is part of a recurring series examining landmark articles in Emergency Medicine, in the style of ALiEM’s 52 Articles.

Discussing:

Andersen et al., NEJM 2003.  A Comparison of Coronary Angioplasty with Fibrinolytic Therapy in Acute Myocardial Infarction.

Main Points:

  1. This prospective randomly-controlled trial investigated whether patients with STEMIs who presented to community hospitals would benefit from transport to specialized centers for percutaneous coronary intervention (PCI) rather than remaining at the local hospital for fibrinolysis. The authors demonstrated an almost 5% reduction in reinfarction rate at 30 days between the two groups.
  1.  STEMI patients that presented to community centers and received aspirin+metoprolol+heparin+PCI within 2 hours, including transfer time, had statistically significantly fewer reinfarctions at 30 days than the STEMI patients who remained at the initial facility andon alteplase+aspirin+metoprolol+heparin.  Ultimately, PCI was shown to be superior to fibrinolytic if available in a timely fashion.

Background:

It is now an established tenet that timely PCI in an experienced center by experienced interventionalists is the best treatment for STEMI.  Historically, with no PCI available at the presenting facility, STEMI patients received anticoagulation and fibrinolytics.  But there were obvious and dangerous concerns in applying a “PCI-or-bust” policy universally, as there are only so many PCI centers to drive patients to, and “time is myocardium.”  So the best treatment for the patient with a STEMI in the middle of the proverbial forest was unknown.  Lyse or transfer?  This study made significant progress towards helping us answer this question.

Methods:

1572 patients were enrolled, 1129 from 24 referral hospitals and 443 from 5 PCI centers.  All of these patients were randomly assigned to receive lysis & anticoagulation (LA) or anticoagulation & PCI (APCI), with the patients from the referral hospitals therefore being transferred for their PCI.  And yes, patients who presented to PCI centers and were assigned LA therefore did not receive PCI.  Risk characteristics of all the patients were similar.  LA patients received 300mg aspirin PO, 20mg metoprolol IV, an “accelerated” alteplase treatment (15mg bolus + 0.75mg/kg over 30min + 0.5mg/kg over the next 60min), and unfractionated heparin for 48h (5000U bolus + infusion titrated to aPTT 70-90sec).  APCI patients received 300mg aspirin IV, 20mg metoprolol IV, unfractionated heparin (10,000U bolus + infusion during procedure to activated clotting time 350-450s).  In patients receiving PCI, GPIIb/IIIa blockers were given at discretion of proceduralist, arteries were treated only if stenosed >30% or if TIMI “flow grade” was <3, non-infarct-related arteries were NOT intervened on, and all patient received Ticlodipine (500mg) or Clopidogrel (75mg) for 1 month afterwards.  The primary endpoint was a composite of death from any cause, clinical reinfarction, or disabling stroke at 30 days follow up.

Results:

  • For patients presenting to PCI centers, there was a 45% reduction in composite outcome with PCI, from 12.3% in the LA group to 6.7% in the APCI group (P = 0.05).
  • For patients presenting to referral hospitals, there was a 40% reduction in the composite outcome with PCI, from 14.2% in the LA group to 8.5% in the APCI group (P = 0.002)
  • Driving the difference within the composite outcome was clinical reinfarction: 1.6% in all APCI vs 6.3% in all LA (P =  0.001).  Differences in death and stroke rates at 30 days were not statistically significantly different between all APCI and all LA patients, whether they were transferred to a PCI center or were already there.
  • The median distance from referral site to PCI center was 50 km
  • Transfer was highly protocolized, with emphasis on shaving-off every precious second of ischemic time.  This cooperation and efficiency resulted in 96% of referral patients landing on the nearest participating PCI table in 2 hours or less.
  • The study was stopped after the 1129 patients, when the third interim analysis showed referral APCIs were reinfarcting less than the referral LAs; this was built into the design as a study cutoff as it implies that APCI is better in both settings.

Discussion:

  • The bottom line is the balance between the proven benefits of PCI and the ischemic time on the myocardium.  There are many variables at play in the “lyse vs transfer (vs both)” decision (see below). These variables include: location and severity of the ischemia, comorbidities and stability of the patient, EMS capabilities, distance, receiving PCI center experience, available medications, etc.  The decision may not always be clear, every patient is probably different, and there is an overwhelming amount of research on this topic.  Do your best.
  • Implementing the airtight transfer logistics they executed here is an obstacle, science aside.
  • In hindsight, your heart has to go out (no pun intended) to the 12.3% of LA patients who presented to a PCI center, got heparin & alteplase, and had a poor outcome.  Their willingness to participate has certainly saved lives.
  • Did you notice that the referred APCI patients did not receive fibrinolysis, only asa, metoprolol, and UFH?  The older research on immediate PCI after fibrinolysis showed no benefit and increased adverse effects.  New and ongoing research on “facilitated PCI,” or PCI after fibrinolysis, using ever-advancing interventional equipment and techniques, may be changing this for some high risk patients for whom PCI is not available within 90 minutes.  For further reading, see these:

Herrmann HC, et al.  Benefit of facilitated percutaneous coronary intervention in high-risk ST-segment elevation myocardial infarction patients presenting to nonpercutaneous coronary intervention hospitals.  JACC Cardiovac Interv.  2009 Oct;2(10):917-24.

Ellis SG, et al.  Facilitated PCI in patients with ST-elevation myocardial infarction.  N Engl J Med. 2008 Maay 22;358(21):2205-17.

Ellis SG, et al. Facilitated percutaneous coronary intervention versus primary percutaneous coronary intervention: design and rationale of the Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial. Am Heart J. 2004; 147: E16.

Level of Evidence:

Based on the ACEP grading system for therapeutic questions this study was graded level I.

Surprises:

The study inclusion criteria was defined as the symptoms for greater than 30 minutes, but less than 12 hours with associated cumulative ST-segment elevation of at least 4mm in at least two contiguous leads.

Resident Reviewer: Dr. Kazakin
Faculty Reviewer: Dr. Siket

Just another cellulitis, or not?

This is part of a recurring series examining landmark articles in Emergency Medicine, based on ALiEM’s 52 Articles.

Discussing: Wong, C. Khin, L. Kien-Seng, H. Kok-Chai, T. Cheng-Ooi, L. “The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: A tool for distinguishing necrotizing fasciitis from other soft tissue infections.” Crit Care Med, 2004, Vol 32(7). 1535-1541.

Main Points:

  1. Developed in a 2004 retrospective observational study, the LRINEC score uses routine laboratory studies alone (CBC, BMP, CRP) to stratify patients with soft tissue infections into high-, moderate-, and low-risk for necrotizing fasciitis.
  1. Using a cut-off value of 6, the PPV was 92% and NPV was 96%; though approximately 10% of patients with necrotizing fasciitis still had a LRINEC score < 6, stressing that this is only a diagnostic adjunct for what is ultimately a clinical diagnosis.

Background:

Necrotizing fasciitis is a rare, rapidly progressive soft tissue infection that is potentially limb and life threatening. Delayed recognition correlates with a higher mortality rate, though early in its course, the disease may be difficult to distinguish from cellulitis or abscess. The purpose of this study was to develop a diagnostic scoring system to differentiate necrotizing fasciitis from other soft tissue infections.

Details:

This was a retrospective observational study divided into a developmental cohort of 314 patients and validation cohort of 140 patients at two teaching tertiary care hospitals in Singapore. The developmental cohort consisted of 89 consecutive patients admitted for necrotizing fasciitis and 225 control patients randomly selected from patients admitted with severe cellulitis or abscess during that same period.

The definitive diagnosis of necrotizing fasciitis was based on characteristics during operative exploration: the presence of grayish necrotic fascia, demonstration of a lack of resistance of normally adherent muscular fascia to blunt dissection, lack of bleeding of the fascia during dissection, and the presence of foul-smelling “dishwater” pus. The diagnosis of severe cellulitis or abscess was based on clinical impression of severe infection in documentation, the use of parenteral antibiotics for > 48 hours, and abscess (when present) requiring surgical debridement.

Thirteen variables from biochemical and hematologic tests done on admission were analyzed, including age, gender, total WBC, hemoglobin, platelet count, serum sodium, potassium, chloride, glucose, urea, creatinine, CRP, and ESR. To construct a diagnostic scoring system, these factors were entered as categorical variables. Six criteria – total WBC, sodium, glucose, serum creatinine, and CRP – were found to be independently predictive of necrotizing fasciitis, each worth 0, 1, 2, or 4 points for a total of 13 points.

This score was then retrospectively “externally validated” on a separate cohort of 56 consecutive patients with necrotizing fasciitis and 84 control patients with severe cellulitis or abscess seen at a separate hospital during a similar time period.

Patients were classified into three groups: low (LRINEC < or = 5), moderate (LRINEC 6-7), or high (LRINEC > or = 8) risk. These risk groups corresponded to a probability of developing necrotizing soft tissue infections of <50%, 50-75%, and >75%, respectively. A LRINEC score greater than or equal to 6 yielded a PPV of 92% and NPV of 96%. Eighty-nine and 92.9% of patients with necrotizing fasciitis had a LRINEC score of 6 or greater in the developmental and validation cohorts, respectively; whereas only 3.1% and 8.4% of control patients in the corresponding cohorts had a score of 6 or greater. The authors concluded that patients above this cutoff of 6 should be carefully evaluated for the presence of necrotizing fasciitis.

Commentary:

The advantage of the LRINEC score, as the authors mention, is that the variables used are routinely obtained when assessing severe soft tissue infections (CBC, BMP, CRP). Another cited advantage is the potential to detect clinically early cases of necrotizing fasciitis.

There are several limitations. Approximately 15% of the data sets were incomplete with respect to the CRP, and yet in the final model, CRP is the most heavily weighted (four points, with no other variable being weighted more than two points). Other potentially useful laboratory markers, such as CK, were not included in the analysis.

While the LRINEC score may be useful in identifying patients at high risk for necrotizing fasciitis, it is less useful in ruling out the diagnosis. In this study, approximately 10% of patients with necrotizing fasciitis had a LRINEC score of less than 6. This highlights the importance of recognizing the clinical features (toxic-appearing patient, pain out of proportion to skin findings, crepitus, rapid progression, bullous lesions, skin necrosis) of a disease that is ultimately diagnosed only in the operating room.

Results from subsequent studies have been even less optimistic. Based on the cutoff of 6, a small retrospective study in 2009 by MJ Holland yielded a sensitivity of 80%, specificity of 67%, PPV 57%, NPV 86% for diagnosing necrotizing fasciitis. A larger retrospective study by Liao et al. in 2012 demonstrated a sensitivity of 59.2%, specificity of 83.8%, PPV 37.9%, and NPV 92.5%. Finally, there have been no prospective trials yet validating the LRINEC score or demonstrating implementation of the score leads to earlier diagnosis or improved outcomes.

How do/will you use the LRINEC score?

Relevant articles:

Wilson, MP. Schneir, AB. “A case of necrotizing fasciitis with a LRINEC score of zero: clinical suspicion should trump scoring systems.” J Emerg Med. 2013 May; 44(5):928-31.

Liao, Chun-I. Lee, Yi-Kung. Su, Yung-Cheng. Chuang, Chin-Hsiang. Wong, Chun-Hing. “Validation of the laboratory risk indicator for necrotizing fasciitis (LRINEC) score for early diagnosis of necrotizing fasciitis.” Tzu Chi Medical Journal. 2012 24: 73-76.

Holland MJ. “Application of the Laboratory Risk Indicator in Necrotising Fasciitis (LRINEC) score to patients in a tropical tertiary referral centre.” Anaesth Intensive Care. 2009 Jul;37(4):588-92.

Chan, T. Yaghoubian, A. Rosing, D. Kaji, A. deVirgilio, C. “Low sensitivity of physical examination findings in necrotizing soft tissue infection is improved with laboratory values: a prospective study.” Am J Surg. 2008 Dec; 196(6):926-30.

 

Resident author: Roger Wu, MD
Faculty reviewer: Matthew Siket, MD, MS

Infections bite! Antibiotic prophylaxis for mammalian bites

This is part of a recurring series examining landmark articles in Emergency Medicine, in the style of ALiEM’s 52 Articles.

Discussing:  Medeiros, I, and H Saconato. “Antibiotic prophylaxis for mammalian bites.”  Cochrane database of systematic reviews Online 2 (2001) : CD001738.

Main Points:

  1. The use of antibiotic prophylaxis for hand bites reduces infections
  1. There is weak evidence supporting the use of antibiotic prophylaxis after human bites to reduce infections (based on one study)

Background:

Mammalian bites account for up to 1% of all ED visits and administration of prophylactic antibiotics is based on studies with insufficient power to determine true efficacy. In order to gather enough cases to sufficiently power a study, The Cochrane Collaboration did a meta-analysis of randomized trials considering the value of antibiotic prophylaxis in human and other mammalian bites. The goal of this analysis was to determine if the use of antibiotics in mammalian bites is effective in preventing bite wound infection.

Eligible studies were searched and retrieved based on inclusion criteria (see details) by two reviewers. Relevant data to answer the study question were extracted, risk of bias was assessed for included studies, and subgroup analysis was performed based on intention to treat of the eight final studies chosen.

For dog bites, there was no statistically significant reduction in infection rate after prophylactic antibiotics (4% (10/225)) versus control (5.5% (13/238)). Only one trial analyzed human bites and the infection rate was significantly lower in the antibiotic group (0/33) versus the control group (47% (7/15)) (OR 0.02, 95% CI 0.00 to 0.33). The infection rates for hand bites were significantly reduced by antibiotic administration (2% vs. 28% in control group) (OR 0.10, 95% CI0.01 to 0.86, NNT=4, 95% CI 2 to 50). There appeared to be no significant difference in infection rate with antibiotic prophylaxis for cat bites, when separating out wound type (laceration vs. puncture), or for bites on body parts other than the hand.

Pitfalls of this meta-analysis:

  1. The antibiotics chosen for prophylaxis were not consistent across studies, and no more than two studies used the same antibiotic. In some studies, the antibiotic used was inappropriate for coverage of mixed anaerobes and aerobes, which is common in many mammalian infections.
  2. The predominance of included patients suffered dog bites (463/522) compared to cats (11/522) or humans (48/522), so the results are skewed heavily toward one species of bite.
  3. Only five studies reported LTFU and three of these had rates over ten percent. Four studies did not even include LTFU numbers, and an intention to treat analysis could not be performed in these. This may bias the results toward no effect since those who did not go on to have an infection would likely not return to the ED.
  4. Only 25% of the studies used double-blinded methods with a placebo of identical appearance.

Details:

This was a meta-analysis study, with the following inclusion criteria:

  1. Study type: RCTs or quasi-RCTs
  2. Participants: patients with mammalian bites (including humans) if they presented within 24 hours and had no clinical signs of infection.
  3. Interventions: use of antibiotics within 24 hours of injury compared to placebo/no-intervention.
  4. Outcomes measured: proven bacterial infection (clinical signs of infection plus positive culture), presumed infection (clinical signs of infection with negative culture) or absence of infection (no clinical signs).

Nine studies met all inclusion criteria but one study did not separate infection rates for each mammalian species.

Level of evidence:

ACEP Level I for Meta-analysis

Source article: Medeiros, I, and H Saconato. “Antibiotic prophylaxis for mammalian bites.” Cochrane database of systematic reviews Online 2 (2001) : CD001738.

 

You Put a Catheter Where? The Groin May Not be as Dirty as Previously Reported

This is part of a recurring series examining landmark articles in Emergency Medicine, in the style of ALiEM’s 52 Articles.

Discussing:  Marik, P. Flemmer, M. Harrison, W. “The Risk of Cathether-Related Bloodstream Infections with Femoral Venous Catheters As Compared to Subclavian and Internal Jugular Venous Cathethers: A Systematic Review of the Literature and Meta-Analysis.” Critical Care Medicine, 2012, Vol 40(8). 2479-2485

Main Points:

  1. This 2012 meta-analysis demonstrated that catheter-related blood stream infection (CRBI) risk is no different between internal jugular, subclavian, and femoral catheter insertion. The authors demonstrated that previous level 1A guidelines regarding femoral catheter infectious risk were in error.
  2. The overall risk of CRBI is declining over the recent years and likely due to the combination of more precautions at the time of insertion as well as vigilant management of the catheter once placed.

Background:

There is significant morbidity and mortality associated with CRBI. In the United States alone, an estimated 30-60 thousand patient deaths occur annually secondary to this infectious process. In 2011 a clinical recommendation from respected organizations including the CDC’s Healthcare Infection Control Practices Advisory Committee as well as the Infectious Disease Society of America issued a class 1A recommendation to “avoid using the femoral vein for central access in adult patients.” This recommendation would suggest that there is strong supporting data including at least one well performed RCT. The purpose of this meta-analysis by Marik and his colleagues was to call into question the validity of such an absolute statement. Marik and his partner Flemmer performed an exhaustive literature search and were able to find 2 RCTs and 8 cohort trials to include in their meta-analysis. This literature review was more comprehensive then the citations provided by the societies issuing the level 1A recommendations. There study, however, focused solely on the question of CRBI and did not address concerns other concerns associated with central venous access such as injury to nearby structures, DVT, or bleeding.

Details:

This study reviewed more data than the 1A recommendation from the CDC and IDSA and could not find compelling evidence that the femoral vein should be avoided for concerns of CRBI. Furthermore, it appears that the universal precautions that are being used currently have likely led to an overall decrease in CRBI compared to the years past. For example, the rate of CRBI in the United States in 1998 was 5.32/1,000 catheter days and has subsequently dropped to 2.05/1,000 in recent data. The Welsh Healthcare Associated Infection Program which is the largest collection of data and noted that in over 55 thousand catheter days in 2009 and 2010 there were only 0.61/1,000 catheter day infectious risk with no difference between insertion sites. Marik and his colleagues therefore note that the site of preference should “depend on the expertise and skill of the operator and the risks associated with placement.” The authors recommend against using femoral vein catheters in renal transplant patients, patients who would benefit from early mobilization as well as the massively obese due to a subgroup analysis in the Parienti study that noted worse outcomes in these individuals.

The average CRBI density in the compilation of trials was noted to be 2.5 +/- 1.9 per 1,000 catheter days (range 0.6-7.2). In compiling the data it was noted that two of the cohort trials, Lorente and Nagashima, appeared as statistical outliers increasing the heterogeneity of the meta-analysis significantly. It is unclear why these two trials demonstrated a more than two-fold increased risk of CRBI with femoral catheter insertion. If these trials were removed from the data the authors noted that there appeared to be no heterogeneity within the study (RR 1.02, 95% CI 0.64-1.65, p = 0.92, I² = 0%). This study also performed a meta-regression that appeared to demonstrate a significant interaction between the risk of infection and the year of publication (p = 0.01).

Level of Evidence:

Based on the design of this study, including RCTs and cohort trials, with a few limitations this study was graded a level III based on the ACEP Clinical Policy Grading Scheme for meta-analyses.

Surprises:

In many aspects of medicine it is curious to see how wide practice variation can be, especially when considering geographic and healthcare system influences. This notion is highlighted by reviewing the different guidelines within this meta analysis by various public health/safety committees across the United States and United Kingdom.

Relevant articles:

Lorente, L. Henry, C. Martin, MM. et al. “Central Venous Catheter-Related Infection in a Prospective and Observational Study of 2, 595 Catheters.” Crit Care, 2005 9. R631-5

Nagashima, G. Kikuchi, T. Tsuyuzaki, H. et al. “To Reduce Catheter-Related Bloodstream Infections: Is the Subclavian Route Better than the Jugular Route for Central Venous Catheterization?” J Infec Chemother, 2006 12. 363-65

Parienti, JJ. Thirion, M. Megarbane, B. et al. “Members of the Cathedia Study Group: Femoral v. Jugular Venous Catheterization and Risk of Nosocomial Events in Adults Requiring Acute Renal Replacement Therapy: A Randomized Controlled Trial.” JAMA, 2008 299. 2413-22

Source Articles:

Marik, P. Flemmer, M. Harrison, W. “The Risk of Cathether-Related Bloodstream Infections with Femoral Venous Catheters As Compared to Subclavian and Internal Jugular Venous Cathethers: A Systematic Review of the Literature and Meta-Analysis.” Critical Care Medicine, 2012 Vol 40(8). 2479-2485

By

Anatoly Kazakin MD