An evidence-based emergency medicine podcast. The Washington University Emergency Medicine Journal Club podcast provides an excellent way to keep up with the medical literature, improve patient care, and increase understanding of evidence-based medicine. Each month we ask a clinical or operational question pertinent to the practice of emergency medicine. We then discuss the four articles most relevant to that question in an attempt to determine the most evidence-based approach to patient care.
You are a fourth-year resident working in TCC one overnight when you (not the patient) begin experiencing pain in your right flank that radiates into your right lower abdomen and groin. The pain is colicky and intermittent and increases in severity to the point that you are in tears. You go and tell your attending, Dr. Wagner, who responds “at least I didn’t make you cry this time.” He tells you to get back to work and stop complaining, but after another thirty minutes the pain is so intense that you are no longer perform your duties as a physician. The back-up person is called in and you are placed in a treatment room to be seen as a patient.
The intern enters the room and notes that you are writhing in pain and are unable to sit still. Your vitals are stable. You have mild right CVA tenderness, no abdominal tenderness, and a normal genital exam (for someone of your gender). Your lungs are clear and other than tachycardia your cardiac exam is unremarkable.
The intern clearly believed that you are suffering from renal colic and wishes to practice their “shared decision-making” skills with you and begins a discussion of the diagnostic options. The options include the following:
1. Check your labs, including a urinalysis (UA), and practice expectant management;
2. The intern can personally perform a bedside ultrasound (US) of your kidneys to evaluate for hydronephrosis;
3. The ED attending can perform a bedside US;
4. You can wait for a formal US to be performed in the morning;
5. A computed tomography (CT) scan can be ordered.
You consider your options while awaiting the IV dilaudid you requested, weighing the risks of radiation exposure, the delay in obtaining a formal US, and the potential loss of accuracy with a bedside ultrasound. You wish you could get on the computer to perform a literature search to find the best option, but choose instead to black out from the pain, welcoming the darkness that enfolds you…
PICO Question:
Population: Adult patients with presumed ureteral colic
Outcome: Diagnostic accuracy, missed alternative diagnoses, need for urologic intervention
Search Strategy:
Having seen a published study in the New England Journal of Medicine that your institution participated in, you choose to include this article (Smith-Bindman 2014). Having such a broad topic, you ask one of your ultrasound experts for additional articles. She sends you a bevy of relevant articles, from which you select an additional three titles to include.
Bottom Line:
Ureteral colic remains a common diagnosis in emergency departments in the United States, where it accounts for over 2 million annual visits. Computed tomography (CT) as a diagnostic imaging modality has seen a dramatic increase in use for the evaluation of ureteral colic, despite growing concerns regarding exposure to ionizing radiation. Ultrasound, on the other hand, has seen very little change in its use in the US, being used in ~6.9% of cases of suspected ureteral colic in 2008. This is in stark contrast to care in Canada, where ultrasound is the preferred imaging modality, being utilized in ~70% of patients who undergo imaging.
One observational study conducted in Ontario, CA evaluated the utility of US in renal colic (Edmonds 2010). There were 817 ED-ordered renal ultrasounds for the evaluation of kidney stone. A normal ultrasound in these patients was associated with a decrease in the need to undergo a CT scan, and correctly identified a population at very low risk of requiring a urologic intervention. In patients with a normal ultrasound, 14% underwent CT scanning within the next 90 days, and one 0.6% required a urologic procedure. Among those with either a visualized stone or indirect evidence of a stone, around 30% and 18% underwent CT scanning, respectively, and around 6% in each group required a urologic procedure.
When ultrasound is used as an initial diagnostic imaging modality, it results in a significant decrease in cumulative radiation exposure without an increase in serious adverse events. In one multicenter US study (Smith-Bindman 2014), patients were randomized to an initial imaging modality of either CT scan, bedside ultrasonography performed by an emergency physician, or ultrasonography performed by a radiologist. The mean cumulative radiation dose over the next months was lower in the bedside and radiologist-performed ultrasound groups than in the CT group (10.1 mSv and 9.3 mSv, respectively, vs. 17.2 mSv). The rate of adverse events in the three groups was 12.4%, 10.8%, and 11.2%. The median ED length of stay was found to be lower in the bedside ultrasound group compared to the other two groups. These results suggest that use of ultrasound as an initial imaging modality is both safe and results in decreased radiation exposure.
Bedside ultrasound imaging use by emergency physicians has continued to increase, and its use has become a requirement for graduating emergency medicine residents. However, proficiency with ultrasound varies greatly with level of training and experience. The effect of level of training on the diagnostic accuracy of ultrasound in suspected renal colic has been evaluated in a prospective observational study (Herbst 2014). For the detection of hydronephrosis, using CT as the gold standard, diagnostic accuracy of bedside ultrasound was fair in the hands of fellowship trained emergency physicians (LR+ 4.97) but was poor in the hands of non-fellowship trained attendings, experienced residents, and inexperienced clinicians (LR+ 2.78, 2.39, and 2.07, respectively). For the detection of moderate hydronephrosis, the positive LRs were much better (22.52, 8, 4.03, and 4.15). One could argue that the detection of moderate hydronephrosis is much more likely to alter patient management than the detection of any hydronephrosis.
The diagnostic evaluation of ureteral colic has three main goals: 1) confirmation of the presence of an obstructing ureteral stone; 2) evaluation for the presence and degree of hydronephrosis; and 3) exclusion of other potentially serious alternative causes of patients' symptoms. Many would argue that for the majority of patients, this last goal is the main priority when considering a diagnostic imaging modality. The reported diagnostic accuracy of ultrasound varies widely in the literature and is typically better at detecting larger stones (Patlas 2001, Fowler 2002, Ripolles 2004). It could be argued, however, that the goal of ultrasound is not to detect the stone itself, but rather to evaluate for the degree of hydronephrosis, and hence determine the need for intervention. It therefore seems reasonable to utilize ultrasound in patients in whom the probability of an serious alternative has been deemed to be low, reserving CT for those where the concern is higher.
The STONE score is a retrospectively derived and prospectively validated clinical decision rule for evaluating the probability of a patient having renal colic. Based on five factors (sex, duration of symptoms, race, presence of nausea and/or vomiting, and hematuria) a score of 0-13 is assigned. Patients with a score of 0-5 were found to have an 8-9% prevalence of kidney stones, compared to a prevalence of 88-89% in those with a score of 10-13. Patients in the high prevalence category had a low rate of alternative diagnoses found on CT scan (1.6%). It would be reasonable, therefore, to forego CT scanning, and potentially ultrasound as well, in patients with a high stone score, while considering CT for those with a low score. Patients with a moderate score (prevalence of ~50%) could undergo ultrasound as an initial imaging modality.
Epinephrine in Out-of-Hospital Cardiac Arrest
Feb 04, 2015
Show notes
Journal Club Podcast #19: January 2015
This month I sat down with EMS physician Dr. Bridgette Svancarek and talk all about epinephrine, and whether it really does any good...
You are doing an EMS ride-along during your EMS elective and get a call for a 70-year old male in cardiac arrest. The paramedic hits the lights and sirens and you're on scene in five minutes. The fire department has already arrived and CPR is in progress. They tell you that the patient was watching TV with his wife when he collapsed about 15 minutes prior to their arrival. He did not receive any bystander CPR and was pulseless and apneic on their arrival.
You and the EMS team take over CPR and bag the patient while hooking up the monitor. He is found to be in asystole and the paramedic grabs an amp of epinephrine. You place a supraglottic airway, he gets the epinephrine, and you load him up while continuing good, uninterrupted chest compressions. He gets two more rounds of epi en route and gets a pulse back.
On arrival to the ED he has a pulse, is mildly hypotensive, but has no spontaneous breaths and his pupils are fixed and dilated. You know that giving epinephrine in cardiac arrest is the standard of care, but wonder what effect it really has: does it improve ROSC, and if so does it actually improve neurologic function down the road. You wonder if there is really any evidence to support its use at all. You head to the computer and start searching...
PICO Question:
Population: Adult patients with atraumatic out-of-hospital cardiac arrest
Comparison: Standard CPR without epinephrine administration
Outcome: Return of spontaneous circulation, survival to hospital admission, survival to hospital discharge, survival with a good neurologic outcome
Search Strategy:
A PubMed search was performed using the search terms “(out of hospital cardiac arrest) AND (epinephrine OR adrenaline).” The search was limited to humans, resulting in 207 citations (http://tinyurl.com/lsgy63r). These were searched and two randomized controlled trials, one observational trial, and a systematic review were chosen for inclusion.
Bottom Line:
Epinephrine is currently recommended in the management of out-of-hospital cardiac arrest (OHCA) by both the American Heart Association and the European Resuscitation Council despite a paucity of clear evidence that it improves patient-centered outcomes. This lack of evidence has led some clinicians to question the use of epinephrine in cardiac arrest. The primary proposed benefit of epinephrine has been an increase in coronary perfusion pressure, which has been demonstrated in animal studies. While no placebo-controlled human studies have confirmed these findings, high-dose epinephrine has been shown to increase coronary perfusion to an even greater extent than low-dose epinephrine. However, this dose-response relationship does not necessarily confirm the benefits of epinephrine. While high-dose epinephrine has been shown to improve rates of return of spontaneous circulation (ROSC), it does not improve the more clinically relevant outcome of survival to hospital discharge (Gueugniaud 1998, Vandycke 2000). This may be in part due to reduced microcirculatory cerebral blood flow caused by epinephrine, resulting in worse neurologic outcomes among survivors.
There have been several observational studies evaluating the use of epinephrine in OHCA with varying results (Herlitz 1995, Holmberg 2002, Ohshige 2005, Wang 2005, Ong 2007, Yanagawa 2010). The largest of these studies (Hagihara 2012) prospectively evaluated outcomes in over 400,000 patients in Japan. The authors found that while epinephrine use was associated with a significant increase in ROSC (adjusted odds ratio [AOR] 2.01, 95% CI 1.83-2.21), it was also associated with significant decreases in survival at one month (AOR 0.71, 95% CI 0.62-0.81) and survival with good neurologic function, as defined by a cerebral performance category (CPC) score of 1 or 2 (AOR 0.41, 95% CI 0.33-0.52).
There has been, to date, one randomized controlled trial comparing the use of epinephrine with placebo in the management of OHCA (Jacobs 2011). While this study demonstrated improvements in survival to hospital discharge with the use of epinephrine, this result did not achieve statistical significance (OR 2.2, 95% CI 0.7-6.3). The study was afflicted, unfortunately, by a small sample size and was underpowered to detect a potentially clinically significant improvement in outcomes. While the investigators initially planned to perform a large study involving five ambulance services throughout Australia and New Zealand, all but one service withdrew from the study due to ethical concerns.
There has been an additional randomized controlled study evaluating the effectiveness of intravenous drug administration during cardiac arrest (Olasveengen 2009), of which epinephrine is arguably the most important component. This study also demonstrated higher rates of ROSC among patients with IV access initiated by EMS (OR 1.99, 95% CI 1.48-2.67). However, there was no statistically significant improvement in survival to discharge (OR 1.16, 95% CI 0.74-1.82) or survival with a CPC score of 1 or 2 (OR 1.24, 95% CI 0.77-1.98). There was a large degree of crossover in this study, and the authors chose to perform an “as treated” analysis of the data based on epinephrine administration (Olasveengen 2012). This analysis demonstrated a significant decrease in both survival to discharge (OR 0.5, 95% CI 0.3-0.8) and survival with a CPC score of 1 or 2 (OR 0.4, 955 CI 0.2-0.7) when epinephrine was administered. These results must be viewed cautiously, as the reasons for crossover between the groups likely disrupted the prognostic balance afforded by randomization, leading to a poorer baseline prognosis among patients receiving epinephrine. Note that among 418 patients randomized to receive an IV, 42 did not have IV access initiated because they had ROSC; only 12 patients in this group did not have IV access initiated due to futility. Among 433 patients randomized to have no IV access initiated, 27 received IV access only after having ROSC and then rearresting.
The existing data is clearly limited, and the authors of a systematic review on the subject understandably conclude that “although the results…exhibit the paucity of high quality published research supporting the use of epinephrine in OHCA, there is insufficient evidence to support changing current guidelines” (p. 90). Fortunately, a trial has recently begun in the United Kingdom (PARAMEDIC 2: the Adrenaline Trial), which plans to enroll 8000 patients randomized to either epinephrine or placebo. This trial will hopefully further elucidate the efficacy or harm associated with epinephrine and provide statistically significant outcomes data to solidify or change our current practice.
Geriatric Fall Assessment in the Emergency Department
Jan 12, 2015
Show notes
Journal Club Podcast #18: November 2014 Chris Carpenter, Mike Galante, and I get together to talk about two things we all do eventually: growing old and falling down... Click Tab to Expand Articles: Article 1: Identification of fall risk factors in older adult emergency department patients, Acad Emerg Med 2009; 16:211-219. Answer Key. Article 2: Identifying older people at high risk for future falls: development and validation of a screening tool for use in emergency departments, EMJ 2013; 30: 918-922. Answer Key 2. Article 3: Predicting geriatric falls following an episode of emergency department care: a systematic review, Acad Emerg Med 2014; 21:1069-1082. Answer Key 3. Article 4: Prevention of falls in the elderly trial (PROFET): a randomised controlled trial, Lancet 1999; 353: 93-97. Answer Key 4. Vignette: Mrs. C., an 86-year old female, presents to your academic emergency department (ED) via ambulance after an accidental fall at home. She is a recent widower and lives alone, but she reports that she has two adult “children” that live nearby and check on her every day either in-person or by telephone. About 12-hours prior to ED presentation today she was walking to the bathroom from her bedroom when she tripped over something and fall onto her left side. She notes left wrist and left hip pain, but denies loss of consciousness, headache, chest pain, dyspnea, abdominal pain, or focal weakness. She was unable to lift herself off the floor last night and was found by one of her grandchildren in the morning. EMS reports a well-kept home without any obvious cause for her fall. Her vitals are BP 160/85, P 60, RR 16, T 37.4°C, and her room air pulse ox is 100%. She is somewhat overweight and in no apparent distress, although she notes that her left hip and wrist hurt to touch or move. You note no contusions or swelling over the hip or wrist, nor does your physical exam demonstrate any other abnormal findings. Her x-rays of the hand/wrist/forearm/pelvis and hip are unremarkable, as is an x-ray of her C-spine. You are not concerned with an occult scaphoid fracture of her wrist. However, due to her persistent left hip pain you order a MRI of her hip/pelvis and no fracture is demonstrated. With adequate opioid analgesia, Mrs. C’s pain is well-controlled and she is able to ambulate with minimal discomfort so you plan discharge home. You notify Mrs. C and her son of these findings and plan, and call the referring physician to notify her. However, her son asks you how likely it is that Mrs. C will fall again and how to prevent future falls. You’ve just heard Dr. Sam Smith’s Washington University lecture about FOAMed and decide to listen to the Skeptics Guide to Emergency Medicine podcast “Falling to Pieces” about geriatric adult fall-risk stratification in the post-ED period. The podcast discusses a prognostic systematic review on this topic, which you decide to read to learn more. The systematic review provides you with a search strategy to find more published research on this topic. PICO Question: PICO Question #1 Population: Geriatric patients in the ED Intervention: Risk-stratification for falls and injurious falls in the months following an episode of ED care Comparison: None Outcome: Sensitivity, specificity, likelihood ratios for fall-risk PICO Question #2 Population: Geriatric patients in the ED Intervention: Fall-prevention program + post-ED discharge standard care Comparison: Post-ED discharge standard care Outcome: Falls or injurious falls in the post-ED discharge period Search Strategy: You note that the systematic review provides exhaustive (3-pages!) PUBMED and EMBASE search strategies in Data Supplement 1. You decide to go another direction so you conduct a “broad” search using the prognostic study filter using PUBMED Clinical Query and the search term “geriatric fall*” yielding 5 citations, including the systematic review (see http://tinyurl.com/orjnsdk).You obtain the rest of the PICO Question #1 research manuscripts by reviewing the results and the bibliography of the systematic review. For PICO Question #2, you use the therapy study filter on PUBMED Clinical Query and the search term “fall prevention elderly” yielding 71 citations (see http://tinyurl.com/nkb4x9n). Bottom Line: Standing level falls are the number one cause of geriatric trauma-related mortality with 33% of those over age 65-years falling each year (increasing to 50% of those over age 80)! One-in-five falls results in an injury and 44% of individuals with fall-related hospital admissions are readmitted to the hospital within 1-year with 33% 1-year mortality. Fallers represent a population with substantial recurrent healthcare use. A history of falls also predicts post-operative complications in older adults undergoing major elective surgery. Elderly falls frequently precipitate a vicious circle of fear of falling, social isolation, diminished quality of life, and increased short-term mortality. Even those with minor fall-related injuries discharged home from the ED experience recurrent falls, functional decline, and ED returns within 3-months. In 2010, EMRA, SAEM, ACEP, AGS, AMA, and ABEM published emergency medicine resident core competencies for geriatric ED care, which included · In patients who have fallen, evaluate for precipitating causes of falls such as medications, alcohol use/abuse, gait or balance instability, medical illness, and/or deterioration of medical condition. · Assess for gait instability in all ambulatory fallers; if present, ensure appropriate disposition and follow-up, including attempts to reach primary care provider. · Assess and document the presence of comorbid conditions (e.g. pressure ulcers, cognitive status, falls in the past year, ability to walk and transfer, renal function, and social support) and include them in your medical decision-making and plan of care. In addition, ACEP, AGS, ENA, and SAEM jointly wrote and released the “Geriatric ED Guidelines” in 2014 that includes protocol and quality improvement recommendations for fall management in the ED setting. Unfortunately, emergency physicians rarely evaluate fall risk and older adults who present to the ED for evaluation after a fall rarely receive guideline-directed management (Donaldson 2005, Naughton 2012). Where is the disconnect between awareness that geriatric falls are a prevalent and clinically important problem? The Knowledge Translation Pipeline (Figure) provides a framework to understand. Awareness by ED providers that geriatric falls is probably not a large “leak” – but awareness that fall-risk screening tools exist, where to find them, and how to interpret them – likely is. The next “leaks” of acceptance and applicability are probably large “leaks” in the pipeline, since healthy skeptics legitimately challenge the quality of ED-based fall research and how valid these findings are for real-world settings. This Journal Club addressed many of those issues. The PGY-I paper assessed fall-risk factors for community-dwelling geriatric patients presenting to (and discharged home from) one U.S. ED for any reason except a fall. They identified four risk factors (non-healing foot sores, past falls, inability to cut own toenails, self-reported depression – the “Carpenter instrument” – see box) as independently associated with 6-month fall risk, but this model/risk prediction instrument requires validation followed by feasibility and effectiveness testing before widespread use. They also noted that objective tests of gait and balance do not predict 6-month falls in ED populations, but these performance tests are reliable (Intraclass Correlation Coefficient = 0.95 for distinguishing “normal”, “borderline”, or “abnormal”). The PGY-II manuscript described the “Tiedemann instrument”, a 2 question fall risk stratification tool. Unfortunately, the Tiedemann instrument does not significantly increase or decrease fall risk on individual patients who have been to ED for a fall-related compliant or with a history of multiple recent falls. As in the PGY-I study, they also found that current objective performance tests (like the timed Get up and Go) in the ED do not accurately predict future falls. The PGY-III manuscript was a prognostic systematic review from the Academic Emergency Medicine Evidence Based Diagnostics series. This study found that no risk factor (including past falls and objective tests of gait/balance) accurately increase or decrease the risk of falls in the 6-months following ED discharge. In addition, the only ED fall-risk screening instruments that exist in 2014 are the Carpenter and Tiedemann instruments described above. Of these two instruments, a Carpenter score >1 has a negative likelihood ratio of 0.11 (95% CI 0.06-0.20) and most accurately identifies older adults at lower risk of falls. Neither instrument accurately identifies the subset at greater risk of falls. Based upon the sensitivity/specificity (93% and 61%, respectively) of the Carpenter instrument at threshold >1, benefit of fall-risk intervention derived from the PROFET study (20% absolute risk reduction), and hypothesized risk of fall-screening of 0.5% and risk of intervention in patient without fall-risk 2%, the test threshold was estimated at 7% and the treatment threshold at 27%. In other words, continuing to assess fall-risk in patients at less than 7% risk may harm more patients than are helped. Similarly, continuing to assess fall-risk in those with >27% risk may also harm more patients than are helped. The PGY-IV manuscript evaluated a fall-prevention intervention in England, but their approach was not really ED-based and the resources available to these investigators via the British National Healthcare System are generally unavailable in the U.S. Nonetheless, they found that community-dwelling adults over age 65 who visit the ED following a fall demonstrate reduced fall rates (Number Needed to Treat to prevent one fall = 5) with an intensive medical evaluation and occupational therapy home safety assessment in the weeks following the index fall. Replication of these results necessitates a universal healthcare system where every patient has insurance and a primary care physician, as well as access to a one-stop shopping Day Hospital for multi-disciplinary assessment when indicated based on the medical evaluation. In addition to these system-level requirements, future studies should evaluate real-time ED based interventions, using validated fall-risk screening instruments, and assess frailty, dementia and health literacy as confounding variables. Although this research fails to provide a definitive fall screening strategy recommended by AGS/BGS Fall Guidelines, ACEP/SAEM Geriatric ED Guidelines, and EM resident core competencies, the status quo is unacceptable and the quantitative summary estimates of fall incidence and risk factor accuracy and reliability provide an evidence basis on which clinicians, nursing leaders, administrators, educators, policy-makers, and researchers can build. Fall prevention (both risk stratification and interventions) in ED settings has been disappointing and largely unsuccessful. No single risk factor significantly increases or decreases the risk of 6-month falls for geriatric ED patients. In one single-center study, the “Carpenter instrument” identified low-risk patients (LR- 0.11), but additional research is needed to reproduce these results and no instrument accurately identifies high-risk patients. The ideal fall risk screening instrument would be accurate and reliable, sufficiently brief for routine ED use by clinicians, nurses, or ancillary staff, and not require equipment that is not routinely available in the average ED. Accurate assessment of post-ED fall risk also has implications for fall prevention intervention studies. Since fall risk is unlikely to remain static throughout an episode of ED care (or for the 6-months following an episode of ED care), the fluid nature of fall vulnerability suggests that within-ED and post-ED repeat fall-risk assessment is logical (but never studied). In addition, since a one-size-fits-all approach to fall prevention has been largely unsuccessful, more accurate fall-risk stratification could provide feasible, targeted strategies upon which to focus interventions towards the unique fall profile of the individual patient using adaptive clinical trial design. Several attendees at Journal Club suggested that health-literacy appropriate ED discharge instructions that educate patients about fall-risk factors in the home would be worthwhile. Figure 2 below (from Carpenter CR; Falls & Fall Prevention in the Elderly in Geriatric Emergency Medicine Principles and Practice; Kahn JH, Magauran BH, Olshaker JS (eds); Cambridge Medicine 2014, pages 345-346) Incorporating a version of this figure into our fall discharge instructions is a future resident Quality Improvement project. Future ED fall risk instruments need to assess geriatric syndromes (dementia, delirium, depression, and frailty) objectively, evaluate more objective measures of fall outcomes (smart phones, body sensors, other passive monitoring devices), and employ readily available ED personnel for fall-risk screening to ensure external validity and reproducibility. Since not every fall is an injurious fall, developing a fall severity grading scale is also worthwhile. Multiple fall-risk instruments have never been assessed in ED settings, including ABCS, CAREFALL, FROP-COM, HOME FAST, Hendrich II, STRATIFY, University of Pittsburgh, New York-Presbyterian, Johns Hopkins, Maine Medical Center, Morse Fall Scale, and the Spartanburg Fall Risk Assessment Tool. In addition, future research should use accepted clinical decision rule methods for derivation & validation and STARD-criteria for the conduct and reporting of diagnostic research. SAEM, AGS, and the NIA published high-yield ED falls research priorities in 2011. Based on our review of the literature, this research agenda remains unchanged in 2015. 1) Can high-risk geriatric fallers who require admission or expedited outpatient evaluation be identified in the ED? 2) Can simple and feasible interventions reduce fall or injurious fall rates after the ED visit? 3) Could rapid response teams or special ED-associated units evaluating geriatric adults at increased risk for recurrent falls reduce fall-related injuries and improve the efficiency of inpatient resource utilization? 4) Can hospital-at-home models for management of high-risk fallers be developed, and what are the characteristics of models that successfully lower falls rates? 5) What are the key elements of electronic information systems that facilitate point-of-care risk stratification and communication of high-risk finds to emergency providers and primary care physicians?
It's a typical TCC shift when you hear yelling coming from the ambulance bay. You run over to find an apneic patient has just been pushed out of a car that then sped off. As you place him on a gurney and move him into the emergency department (ED), you notice fresh track marks, a recently used syringe on the ground, and drug paraphernalia sticking out of his pockets. You begin to bag him and notice that he has pinpoint pupils and no other signs of trauma. You administer an atomized dose of intranasal naloxone and continue bagging him until he begins to breathe adequately. A few minutes later, the nurse comes to get you to let you know that the patient is now awake and wants to go. You go back to the room and tell him that he needs to stay since you are worried that he will stop breathing once the naloxone wears off. You offer him a turkey sandwich as a compromise to get him to stay and go to see the new patient with respiratory distress.
You have just finished intubating the patient with respiratory distress and are getting ready to place a central line in a patient with severe sepsis when the nurse comes to let you know that your overdose patient is getting belligerent and that you need to do something. Before you even have a chance to calm him down, he tells you that he is leaving now and angrily asks who gave you permission to bring him here, wants to know who is going to give him money to get home, and wants to know why someone filled his pants with ice. You tell him he cannot go yet, and if he doesn't calm down, you will have to call security. After going through this 2 more times, he has now been in the ED for approximately an hour. You offer him chemical dependency information and discharge him. After he leaves, you realize that neither you, the patient, the nursing staff, or the patient sharing a trauma room with him enjoyed this experience and wonder if it was really necessary to go through all that or if you could have just let him go much earlier.
PICO Question:
Population: Patients with acute opioid overdose requiring naloxone administration with return to baseline.
Intervention: Transport to the hospital by EMS or ED observation.
Comparison: Immediate release by paramedics or from the ED
Outcome: Rebound opioid toxicity resulting in death or anoxic brain injury, or requiring additional administration of naloxone.
Search Strategy:
PubMed was searched using the following strategy: “naloxone AND overdose AND (release OR transport OR recurrence)” (http://tinyurl.com/n937tns). The 57 resulting citations were searched for observational or randomized controlled trials evaluating the safety and efficacy of immediate release for patients responding to naloxone after opiate overdose. The following 4 articles were selected for review.
Bottom Line:
Opioid overdose remains an increasing problem in the United States, resulting from the high prevalence of heroin abuse and the increasing abuse of prescription opioids. Death due to opioid overdose has been increasing in recent years, prompting some communities (such as Boston, MA) to institute programs for bystander administration of naloxone to reverse toxicity. Whether administered by a bystander or EMS, naloxone typically results in adequate reversal of toxicity. In most EMS systems, such patients are then transported to an ED for observation, given the theoretically short-lived action of naloxone and concerns for recurrent toxicity. Some have proposed that such observation is unnecessary, and that such patients can be released at the scene as long as they return to their baseline. We sought to evaluate the evidence for such a proposed “treat and release” protocol, and to assess the incidence of recurrent toxicity following naloxone administration.
In those studies involving the treatment and release of patients by EMS, without transport to the hospital, the risk of death from recurrent opioid toxicity was low, ranging from 0% (Vilke 2003, Wampler 2011) to 0.13% (Rudolph 2011). The 3rd of these studies was conducted in Denmark, where a physician is present in the field to assess the patient and make transport decisions. This makes it difficult to extrapolate the study’s results to our EMS system. A strength of this study was Denmark’s centralized database inclusive of all citizens, allowing the authors to easily find anyone that died after being released. In addition, the authors were able to obtain all forensic data surrounding the deaths to determine which were from rebound opioid intoxication and which were from other causes. The former two studies, on the other hand, were conducted in large US cities (San Diego, CA and San Antonio, TX respectively) with more familiar EMS systems, and demonstrated similarly low rates of death due to recurrent toxicity. While no deaths were found in the US studies, it is possible if people died in different counties that they could have been missed, as the US does not have a central database. A fourth study based in Helsinki showed similar results; the authors found no cases of patients dying from recurrent opioid toxicity (Boyd 2006).
A single ED-based study evaluated the risk of toxicity recurrence based on a retrospective chart review (Watson 1998). A Delphi Panel was employed to determine whether rebound occurred following a response to naloxone administration in the ED. In this small study (42 total cases), recurrence of toxicity was identified as either definite or probable in 13 cases (31%, 95% CI 17-45%). Interestingly of the 13 cases, only 2 were noted to have recurrent respiratory depression. The other 11 patients had decreased mental status without any respiratory compromise. The authors later state that neither of the patients with respiratory depression received any specific treatment. As such, it is difficult to determine the significance of their respiratory depression. These results are confounded by differences in baseline patient characteristics from those in our practice as well as the use of a highly subjective outcome. Specifically, nearly 50% of patients in this study presented following suicide attempt, and 81% of cases involved an oral ingestion of opiates. Anecdotally, the large majority of opiate overdoses seen in our setting involve the recreational use of IV heroin, and recurrence rates may therefore be different. Additionally, in those patients receiving naloxone initially, only 27% were noted to have respiratory depression, and thus the indication for naloxone is suspect. Recurrence of toxicity, the primary outcome, was highly subjective and thus determined by a Delphi panel. Only 18 of the 42 cases considered to have had recurrence were deemed “definite,” with the remaining only “probable.” Even in those cases with definite recurrence of toxicity, the exact indication for repeated doses of naloxone remain unclear, and there is no evidence that more serious patient-centered outcomes were prevented in any of these cases.
The bulk of this data supports the “treat and release” strategy adopted by many EMS systems, with the caveat that such a strategy be employed in select patients who have returned to baseline with stable vital signs and are capable of understanding the risks associated with discharge in the field. If patients want to go to the ED, this should still be encouraged as patients could be evaluated for drug related infectious diseases, as well as receive information about addiction treatment and other social services. Transporting the patient against their will, and holding them in the ED, is probably unnecessary and does not seem to be supported by available evidence. However if the patient took a longer-acting opioid such as methadone, it may be prudent to specifically warn them of possible risks associated with these agents as studies did not specifically look at the safety of a “treat and release” strategy in patients exposed to long-acting opioids.
Thrombolytics in Submassive Pulmonary Embolism
Oct 30, 2014
Show notes
Journal Club Podcast #16: September 2014
Maia Dorsett and I chat about thrombolytics, pulmonary emboli, and Muppets. That's right, Muppets...
You are working a day shift in your ED when you meet a generally healthy 55 year-old male who acutely developed chest pain and shortness of breath at home. He tells you that he underwent an orthopedic procedure 10 days prior. He is tachycardic and has an oxygen saturation of 94% on room air. You order an EKG, which demonstrates an S1Q3T3 pattern and a troponin level which is very mildly elevated at 0.12. You think to yourself, “I’ve got this diagnosis” and order a PE protocol CT, which identifies bilateral acute pulmonary emboli with a significant clot burden as well as dilation of the right ventricle. A bedside cardiac ultrasound was suggestive of right ventricular dilatation, so you send the patient to the Cardiac Diagnostic Lab for a formal ECHO, which reveals a markedly dilated right ventricle with flattened septal motion, McConnell’s sign of right ventricle apical hyperkinesis, and tricuspid regurgitation consistent with right ventricular dysfunction in the context of an acute pulmonary embolism.
Given the relatively young age of the patient and his previously normal cardiac function, you consider whether to offer thrombolytic therapy given the degree of right ventricular dysfunction seen on ECHO. However, the patient has a SBP > 110 and is on room-air, and hence does not meet criteria for a “massive” PE. You wonder whether there is any recent data that can help you decide whether to offer thrombolysis in more “submassive” PE. You ask yourself “what can I tell my patient about the effect on his overall risk of mortality and long term functional outcome?”
You begin by reading a previous Washington University Journal Club on this topic from July 2010, at which time the evidence was sparse, and a firm conclusion could not be drawn. You decide to see if any new literature exists, formulate your PICO question, and start your search. Luckily for you, there have been a lot of recently published articles attempting to answer your very question.
PICO Question:
Population: Adult patients with pulmonary embolism and evidence of right heart strain, with stable hemodynamics.
Intervention: Thrombolytic therapy.
Comparison: Anticoagulation with heparin, low molecular weight heparin (LMWH), or novel anticoagulants.
Outcome: Death, hemodynamic collapse, need for intubation, long-term functional outcomes, and quality of life.
Search Strategy:
In addition to the recently published PEITHO study, a PubMed search was performed using the strategy: ((“Thrombolytic Therapy"[Mesh] OR "Fibrinolytic Agents"[Mesh]) AND "Pulmonary Embolism”[Mesh]) with filters for meta-analysis, randomized controlled trial, and limited to the last 5 years (http://tinyurl.com/omwebmt). This resulted in 22 articles, from which 2 RCTs and a meta-analysis were chosen.
Bottom Line:
Venous thromboembolic disease, including both deep venous thrombosis (DVT) and pulmonary embolism (PE), is a prevalent condition, affecting an estimated 300,000 to 600,000 individuals in the US each year (Beckman 2010). Pulmonary embolism alone affects approximately 23 individuals per 100,000 (Anderson 1991). Given the high mortality of nearly 50% (Kucher 2006) in patients with PE and hemodynamic instability - i.e. “massive” PE - guidelines universally recommend considering the use of systemic thrombolytics in such cases (AHA, ESC, ACEP, NICE).
The use of thrombolytic therapy in hemodynamically stable patients with signs of right ventricular (RV) dysfunction - i.e. “submassive” PE - is highly debated. The guidelines vary widely in the their recommendations, from firmly stating “Do not offer pharmacological systemic thrombolytic therapy to patients with PE and haemodynamic stability” (NICE), to noting that there is insufficient evidence to make recommendations (ACEP), to clearly recommending thrombolysis when there is evidence of RV dysfunction or elevated cardiac biomarkers (AHA). In the last year, at least 2 randomized controlled trials evaluating thrombolysis in submassive PE have been published, along with a recent meta-analysis, which dwarf much of the data previously published. As a result, it will be important to review this new data and update existing guidelines accordingly.
While mortality rates in hemodynamically stable patients with PE are much lower than in those with massive PE, ranging from 3% to 15%, the presence of RV dysfunction on ECHO confers nearly double the risk of death (unadjusted risk ratio 2.4), while elevations in cardiac biomarkers confer an even greater increased risk (Sanchez 2008). In addition to potential mortality benefit from thrombolysis, some have theorized a potential to decrease the long-term morbidity associated with large clot burden. The incidence of symptomatic chronic thromboembolic pulmonary hypertension (CTEPH) following venous thromboembolic disease is low, at around 4% at 2 years (Pengo 2004). There is no conclusive evidence that large clot burden, RV dysfunction, or elevated cardiac biomarkers increase this incidence. Prior observational studies have suggested that this incidence is reduced by the use of thrombolytics (Kline 2009), but no randomized trials have supported this finding conclusively.
A prior journal club on this topic conducted in 2010 was limited by the lack of randomized trials assessing patient-important outcomes. We therefore sought to update our findings in light of the recent influx of higher quality evidence in this area. The MOPETT trial evaluated the use of low-dose tPA in those with “moderate” PE, here defined as PE involving 2 or more lobar or main pulmonary arteries. A significant decrease in the incidence pulmonary hypertension was observed (number needed to treat [NNT] 2.4) with no difference in mortality or recurrent PE. Oddly, there were no bleeding events reported in either group. The primary outcome here was unfortunately based on ECHO findings, and does not necessarily translate into patient-important outcomes. In contrast to MOPETT, the TOPCOAT study sought to evaluate functional capacity and quality of life following the use of tenecteplase in patients with PE and either RV dysfunction or elevated cardiac biomarkers. The authors found a reduction in a composite outcome of “adverse events” defined as recurrent PE or DVT, death, poor functional capacity, or poor quality of life (NNT 4.5). However, the groups had similar mortality rates, and it is unclear from the study whether the driving factor for these results was a decrease in patient-important outcomes (quality of life), or surrogate outcomes (ECHO findings). This fact, along with the unfortunate note that the study was stopped early, makes interpretation of these results difficult.
The largest study on this topic to date (PEITHO) was a double-blind study in which patients with both RV dysfunction and an elevated troponin were randomized to either anticoagulation alone, or anticoagulation plus a bolus of tenecteplase. They reported a significant decrease in the combined risk of death or hemodynamic decompensation at 7 days (NNT = 33), but a significant increase in the risk of major bleeding (NNH = 14). Mortality itself was similar in the two groups, and the benefit seen in the primary outcome was derived largely from a decreased risk of hemodynamic decompensation. Given the high risk of bleeding found, particularly intracranial bleeding, it would be important to know the functional outcomes of survivors. It is difficult to fully assess the trade-off in this study between benefit (decreased risk of hemodynamic decompensation) and harm (increased risk of major bleeding).
Finally, a recent meta-analysis (Chatterjee 2014) demonstrated an improvement in mortality, with a NNT of 59 for thrombolysis in all patients with PE, regardless of severity. This mortality benefit was balanced by an increased risk of major bleeding, with a NNH of 18. Specifically, for patients with “intermediate-risk” PE, the mortality benefit was slightly smaller (NNT 65) while the risk of major bleeding was the same (NNH 18). The degree of heterogeneity in the included studies, including poorly defined criteria for “intermediate-risk,” poorly defined criteria for “major bleeding,” and differing routes of administration of thrombolytics, limit our ability to draw firm conclusions from the meta-analysis. For example, the ULTIMA study was included in both meta-analyses, and involved ultrasound-assisted catheter-directed administration of thrombolytics. One could argue that pooling results from such disparate studies make little clinical sense, and one should interpret these results cautiously (if at all).
Despite an influx of new evidence over the last few years, the debate over thrombolysis in “submassive” or “intermediate-risk” PE rages on. Recent studies have failed to show a mortality benefit, whether measured 5 days (TOPCOAT), 7 days (PEITHO), or months (MOPETT trial) after administration, and a trade-off between hemodynamic decompensation and bleeding predominates. Some have proposed longterm functional benefits in those with significant clot burden or evidence of RV strain, but high-quality studies have yet to demonstrate an improvement in patient-important functional outcomes. While MOPPET demonstrated improved pulmonary artery systolic pressures on ECHO, the relationship between such a finding and patient-centric outcomes is unclear at best. The TOPCOAT study demonstrated an improvement in a composite outcome including death, recurrent DVT or PE, ECHO findings, functional capacity, and quality of life, but the contribution from each individual component is unclear, and it is difficult to translate these findings into clinical practice. For now, thrombolysis should be reserved for those with hemodynamic decompensation, or those felt to be at high risk of decompensation whose bleeding risk does not outstrip the potential benefit.
Non-operative Management of Pediatric Appendicitis
Sep 12, 2014
Show notes
Journal Club Podcast #16: August 2014
I sit down with my pediatric EM homies - Drs. Trehan and Horst - and shoot the breeze about pediatric appendicitis...
You are working in the ED in rural Missouri and receive sign out on a ten-year old male presenting with apparent uncomplicated appendicitis. The patient presented with increasing right lower quadrant pain for the past 36 hours, nausea, and anorexia. He did not have a fever and was able to walk into the emergency department. His vital signs are as follows: BP 110/60, HR 85, RR 12, Sat 98% on room air, T 36.5. Your colleague believes that the patient has appendicitis without peritonitis on exam (RLQ pain on palpation, but no guarding or rebound tenderness). Your colleague had already consulted the general surgeon on call who agreed with the physical exam findings, but insisted on an abdominal/pelvis CT (with IV and oral contrast).
The CT revealed acute appendicitis with an appendiceal diameter of 1 cm without phlegmon, abscess, or fecalith. After you receive sign out on this patient, you prepare to transfer him to a children’s hospital as there are no pediatric surgeons at your hospital. However, the family would prefer to be treated at the local hospital, as the nearest children’s hospital is quite far away and it would be a hardship on the family to receive treatment there. Furthermore, the family asks if surgery is truly necessary as a family member recently died due to complications of a surgery. You consider the question, and begin to search the literature to see if there is any evidence that non-operative management of appendicitis in children (with antibiotics) is safe and effective.
PICO Question:
Population: Children with uncomplicated appendicitis
Intervention: Non-operative management with antibiotics
Comparison: Appendectomy
Outcome: Complications (wound infection, perforated appendix); recurrent appendicitis; resolution of symptoms; need for appendectomy despite initial non-operative management.
Search Strategy:
PubMed was searched using the strategy: (nonoperative OR non-operative) AND (appendicitis) AND (children), resulting in 66 citations. The “10 years” publication date filter was applied, reducing the total to 46 results (http://tinyurl.com/mlrljws). The titles and abstracts of these 46 articles were reviewed to assess for relevant studies involving children with uncomplicated appendicitis, and 4 relevant articles were selected.
Bottom Line:
Appendicitis remains a common diagnosis, with an annual incidence of approximately 250,000 in the US; the highest incidence occurs in pediatric patients between the ages of 10 and 19 years (Addis 1990). A total of over 216,00 children required urgent appendectomy in the US between 2006 and 2008 (Masoomi 2012). While the overall complication rate from surgical appendectomy is low (~2.5%), surgery can be associated with significant time out of school for children and time off work for parents. Non-operative management of pediatric appendicitis therefore offers the theoretical advantage of reducing these often ignored societal costs. While studies in adults have demonstrated better pain control, fewer complications, and shorter duration of sick leave with non-operative management (Mason 2012), the evidence is less well-defined in the pediatric population.
We identified a handful of small studies of varying methodological quality for our review. A single randomized controlled trial from Sweden was identified that enrolled 50 children with non-perforated appendicitis found that 2 children out of 24 randomized to non-operative treatment required appendectomy within 3 months; an additional 7 children underwent appendectomy within one year, for an overall 62% rate of avoidance of appendectomy (Svensson 2014). There were no major complications in either group, and the length of stay for the initial hospital admission was shorter in the operative group (median 34.5 hours vs. 51.5 hours, p = 0.0004). The authors reasonably conclude that “nonoperative treatment is feasible and safe.”
Unfortunately, this randomized controlled trial did not evaluate the effect of non-operative management on other important outcomes to parents and children, such as time of work for the parent or time to return to school and normal activities for the child. These outcomes were addressed in a prospective nonrandomized trial from Columbus, Ohio (Minneci 2014). Children with uncomplicated appendicitis with symptoms lasting less than 48 hours were eligible for enrollment. The decision to proceed with surgery or non-operative management was made by the families of eligible patients after counseling using a standardized, scripted presenting process by 1 of 3 trained physicians in order to minimize selection bias. A total of 77 children were enrolled, 30 of whom underwent non-operative management with the remainder undergoing laparoscopic appendectomy. Three children initially managed non-operatively required appendectomy within 30 days of enrollment, for a 30-day success rate of 90% (95% CI 79-100%). Patients in this group had longer initial hospital stays (median 38 vs. 20 hours), but fewer days to return to normal activity (median 3 vs. 16.5), fewer days of missed school (median 3 vs. 5). While quality of life questionnaire scores were slightly higher for the non-operative group, overall parental satisfaction scores were the same for both groups, and were quite high.
Two additional retrospective studies of lesser methodological quality were identified. A case series of 24 patients treated by a single pediatric surgeon in Ontario (Armstrong 2014), 3 out of 12 patients initially managed non-operatively required appendectomy within the follow-up period (median of 6.5 months follow-up). One patient in the non-operative group developed a post-operative infection compared to two in the operative group; none of these required further surgery or led to long-term complications. A final case series from Turkey in which 16 patients with appendicitis treated non-operatively was reviewed (Abes 2007). One patient failed initial non-operative management and required appendectomy after one day of antibiotics, while 2 additional patients developed recurrent appendicitis within one year and required appendectomy. The overall 1-year success rate was therefore 81% (95% CI 57-93.4%). No major complications were reported.
The data, while limited, suggest that non-operative management of pediatric appendicitis with antibiotics is safe and does not result in significant morbidity. It also appears that non-operative management results in less time out of school and a shorter time to return to normal activities, and most likely would lead to less time off work for the parents. It therefore seems reasonable to offer an initial attempt at non-operative management to the parents of select children with uncomplicated acute appendicitis. The final decision will depend on many factors, including the comfort-level of the parents, child, and surgeon, as well as the potential affect of the decision on child and parental activities.
Tranexamic Acid (TXA) for Hemorrhage in Trauma
Jul 27, 2014
Show notes
Journal Club Podcast #15: July 2014
I'm joined this month by Drs. Wes Watkins and Bill Dribben to talk about the use of tranexamic to reduce hemorrhage in trauma patients...
As you are sitting in a break room at the NATO Role 3 Hospital at Kandahar Air Field (KAF) eating your 7th bag of beef jerky and waiting 45 minutes for a 2 minute you tube video to download you hear on the radio that a 9-line MEDEVAC flight is inbound with a severely wounded soldier. The pt arrives and the flight medic relays the history of a 24 y/o active duty army soldier that was on patrol in Southern Afghanistan when a dismounted improvised explosive device (IED) detonated. He had no obvious head injury and a GCS of 15 but suffered significant extremity injuries, blood loss, and multiple traumatic amputations; tourniquets were applied to all 4 extremities. Primary and secondary survey reveals the following injuries: traumatic BKA bilateral LE’s; fragment wounds right buttock; fingers 3-5 traumatic amputation with open metacarpal fracture left hand; fragment wounds left forearm with transection of the ulnar artery and nerve; traumatic AEA amputation right UE; fragment wounds right axillary artery; fragment wounds to neck; and bilateral ruptured TM’s. CT H/C/A/P was negative and C/T/L spine were radiographically normal.
You initiate Damage Control Resuscitation (DCR) and Massive Transfusion (MT) guidelines and the patient received 38 units PRBC’s; 33 units FFP; 4 units of platelets; 30 units of cryoprecipitate; and Tranexamic acid (TXA) 1 g IV in 100 ml NS over 10 min followed by 1 g IV in NS over 8 hr in the ED and OR. In the OR the pt underwent D&I of his wounds with conversion of his LUE injury to a mid-forearm amputation and BLE injuries to AKA’s. Post–op H/H 9.9/26.5 and INR 1.2. Pt was airlifted by a Critical Care Air Transport Team (CCATT) to Bagram Air Field (BAF) for further stabilization. At BAF pt was taken to OR for further wound management and received 10 units PRBC’s, 4 units FFP, 1 unit of platelets, and 10 units Cryoprecipitate. Post-op H/H 11.2/31.8 , platelet count 105, INR 1.2. A chest CT revealed a PE and pt was started on Heparin. His Bun/Cr and K+ began to increase and he was started on continuous renal replacement therapy (CRRT). The patient was then validated for air movement to Landsthul Army Medical Center (LRMC), Germany via CCATT. Prior to flight CRRT was discharged and H/H was 7.2/21, pt was given 2 units PRBC’s and loaded onto the aircraft with follow-up H/H 8.5/25. During the flight, his H/H decreased to 6.8/20 and 1 unit PRBC’s and 1 unit FFP were transfused with increase in H/H to 7.5/22. The pt was safely delivered to the ICU at LRMC.
Total time from point of injury (POI) to LRMC ~ 48 hrs. and 51 units PRBC’s, 38 units FFP, 5 units of platelets, and 40 units cryoprecipitate were transfused. You begin to wonder what affect the TXA really had, and what evidence there is to support its use in military and civilian settings. You sit down to begin your literature search...
PICO Question:
Population: Civilian trauma patients presenting to the ED with hemorrhage requiring massive transfusions.
Intervention: Administration of TXA in the ED.
Comparison: Standard resuscitative measures.
Outcome: Overall mortality, death due to bleeding, thromboembolic events, coagulopathy, transfusion requirements.
Search Strategy:
MEDLINE was searched via PubMed using the strategy “tranexamic acid trauma” resulting in 299 articles (http://tinyurl.com/qxn4c45). The 4 most relevant articles were then chosen.
Bottom Line:
Traumatic injuries represent a significant source of morbidity and mortality worldwide, with hemorrhage responsible for 30% of in-hospital trauma deaths each year. Tranexamic acid (TXA) has been used for decades to reduce bleeding in a variety of situations, including cardiopulmonary bypass, menorrhagia, and upper GI bleeding. TXA is a lysine analog that binds the lysine-binding site on plasminogen and prevents its conversion to plasmin, which would lead to fibrin degradation (Okamoto 1997). This antifibrinolytic property theoretically leads to decreased hemorrhage and blood loss, and would potentially benefit those at risk of bleeding due to significant trauma.
The CRASH-2 (Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage) trial, published in 2010, was an international, multicenter study that sought to evaluate the benefit of TXA in trauma from a global health perspective. Patients were enrolled primarily in low and middle-income countries, where 90% of trauma deaths occur worldwide. Over 20,000 trauma patients from 274 hospital in 40 countries were enrolled and randomized to receive either TXA of placebo. A small but significant reduction in mortality was observed in those patients receiving TXA (absolute risk reduction [ARR] 1.5%, 95% CI 0.49 to 2.47), with a number needed to treat (NNT) of 68. There was no observed increase in the number of vascular occlusive events (PE, DVT, MI, CVA), the most dreaded potential complication of TXA. Critics of the study point mainly to the subjective nature of the inclusion criteria (patients at risk of “significant hemorrhage”) and exclusion criteria (those with clear indications or contraindications to TXA), the low risk of hemorrhage in the study (only half of the patients required transfusion), and differences in transport time and trauma care between the included countries and the United States. Despite these critiques, this study led to the inclusion of TXA in the World Health Organizations list of essential medicines.
A subgroup analysis of data from the CRASH-2 trial attempted to further clarify situations in which TXA would be beneficial in trauma. In this analysis, a reduction in death due to bleeding was noted in those who received TXA less than 1 hour from the time of injury (RR 0·68, 95% CI 0·57–0·82) and those who received TXA between 1 and 3 hours from the time of injury (RR 0·79, 95% 0·64–0·97). Interestingly, a paradoxical increase in the risk of death due to bleeding was observed in those who received TXA more than 3 hours from the time of injury (RR 1·44, 95% CI 1·12–1·84). The authors also evaluated the effect of TXA on death due to bleeding based on initial SBP, GCS, and type of injury, but did not find homogeneity in the results of these subgroup analyses.
A retrospective analysis of 896 patients treated in the military was undertaken using a cohort of patients treat at Camp Bastion Hospital in Afghanistan, of whom 293 (32.7%) received TXA. Both NATO personnel (US and UK military) and Afghan national military personnel were included in the study. Given the observational nature of this study, it is not surprising that patients who received TXA were much sicker than those who did not receive TXA, based on Injury Severity Score (ISS), Abbreviated Injury Scale (AIS), Revised Trauma Score (RTS), initial Glasgow Coma Score (GCS), and systolic blood pressure. Despite have worse baseline prognosis, patients who received TXA had decreased mortality compared to those who did not, with an unadjusted RR for in-hospital mortality of 0.73 (95% CI 0.54 to 0.98). In a subset of patients who met criteria for massive transfusion (requiring 10 or more units of blood within 24 hours), a similar reduction in in-hospital mortality was observed with the use of TXA (RR 0.51, 95% CI 0.32 to 0.83). Multivariate logistic regression analysis revealed that the use of TXA was independently associated with reduced mortality in the massive transfusion subgroup of patients, with an odds ratio for survival of 7.23 (95% CI 3.02 to 17.32).
As in the CRASH-2 trial, differences between patients enrolled in the MATTERs study and those cared for in a civilian US level 1 trauma center make it difficult to apply the results to our patient population. Patients in MATTERs were quite young, with a mean age of 23, and were almost entirely male. Additionally, the mechanism of injury was predominantly explosion, accounting for three-fourths of the patients receiving TXA and over 60% of those not receiving TXA. The remainder of the injuries were due to gunshot wounds, presumably mostly from large caliber, military weapons. The injury patterns involved likely resulted in significantly more hemorrhage than would typically be observed in motor vehicle crashes and smaller caliber gunshot wounds, and the effect of TXA potentially magnified.
To evaluate the effect of TXA on a civilian US population, a retrospective analysis of outcomes was conducted at Ryder Trauma Center in Miami, FL over a 3-year period from August, 2009 to January, 2013. A cohort of 150 patients who were given TXA during that time period (at the discretion of the treating physician) was matched to a similar cohort using propensity matching. Patients were matched based on age, sex, presence of traumatic brain injury, mechanism of injury, systolic blood pressure, need for blood transfusion, and injury severity score (ISS). They found that patients who received TXA had increased mortality (31% v 23%), though this difference was not statistically significant (RR 1.31, 95% CI 0.90 to 1.92). By excluding groups of patients (those that died within 2 hours of arrival, those with TBI, those that received less than 2 liters of blood, and those with a systolic blood pressure over 120 mmHg), the authors were able to find statistically significant increases in mortality with the use of TXA.
While this study would seem to suggest significant harm from the use of TXA in a civilian US trauma center, this seems unlikely. Given that patients who received TXA in this study were taken to the OR more rapidly than their counterparts (median 24 minutes vs. 35 minutes) and required significantly more blood products over the first 24 hours (2,250 vs. 1,999 mLs), it seems likely that this was a baseline sicker cohort of patients who began their course with a more sinister prognosis. Additionally, the observed mortality increase was not statistically significant due to the underpowered nature of the study; while statistical significance was achieved by excluding certain groups of patients, these were subgroup analyses and must be validated prospectively before changing practice. Unfortunately, the authors do not report the incidence of thrombotic events; aside from thrombosis, no reasonable mechanism for the observed increase in mortality can be attributed to TXA
Conclusions
The bulk of the existing evidence suggests that TXA reduces mortality in trauma patients with hemorrhage. This includes data from a cohort of patients with less significant hemorrhage (CRASH-2) as well as a military cohort of patients with significant hemorrhage and those requiring massive transfusion (MATTERs). While the single study performed on US patients revealed a non-statistically significant increase in mortality with the use of TXA, the methodological limitations of this case control trial, and the large disparity of its results compared to other existing studies, bring these results under scrutiny. For now, the evidence suggests that TXA, when given within 3 hours of injury, likely reduces mortality in patients at risk of significant traumatic hemorrhage, and should at least be considered in those requiring massive transfusion protocol initiation.
Antibiotics for Anterior Nasal Packing in Epistaxis
Jun 13, 2014
Show notes
Journal Club Podcast #14: May 2014
I join...myself, to talk about the routine administration of prophylactic antibiotics for anterior nasal packing in epistaxis...
You are working in your community emergency department (ED) one winter afternoon when you encounter Mr. D. He is a 64 year old gentleman with a history of hypertension, who takes amlodipine and a daily 81 mg aspirin. He presents with one hour of continuous right-sided epistaxis. You have him blow his nose to evacuate all of the clot and spray phenylephrine in both nares. You take two cotton-balls, soaked in a mixture of phenylephrine and viscous lidocaine, and place one in each anterior nasal cavity. You then apply a nose clip and leave him alone for 20 minutes.
When you return and remove the cotton-balls, intent on cauterizing the offending area with silver nitrate, you find that there is still a continuous ooze from the right anterior septal mucosa that is too brisk to allow for cautery. You bite the bullet and grab a 5.5 cm Rapid-rhino and insert this in the right nare. After inflating the balloon, you find that you have achieved good hemostasis. You call your on-call ENT to arrange a follow-up appointment in the next 2-3 days for removal of the Rapid-rhino and further assessment of the epistaxis. The ENT agrees to see the patient, and at the end of the call reminds you to send the patient home on oral antibiotics until follow-up. You send the patient home with a prescription for amoxicillin-clavulanic acid.
You are back working again 4 days later, when Mr. D returns to the ED. His nasal packing was removed the day prior without incident and a small area in his nasal mucosa was cauterized successfully by the ENT physician. Mr. D is presenting now with horrible diarrhea and abdominal cramping. As you leave the room and get ready to order a C. diff toxin screen for his stool, you wonder if it’s really worth putting patients with anterior nasal packing on prophylactic antibiotics, given the adverse symptoms often encountered. You decide to check the literature when you get off work.
PICO Question:
Population: Adult patients with anterior nasal packing in place for epistaxis
Outcome: Toxic shock syndrome, sinusitis, otitis media
Search Strategy:
You search PubMed using the terms “epistaxis AND antibiotics,” and identify 200 articles, 3 of which are most relevant to the PICO question (http://tinyurl.com/kcptxrh). Unable to find a 4th article specifically addressing antibiotics in nasal packing for epistaxis, you instead choose an article from the bibliography of one of the selected articles that addresses antibiotic use following septoplasty.
Bottom Line:
Epistaxis is a common problem, with a lifetime incidence of approximately 60% (Gifford 2008). While the majority of cases do not require medical attention, epistaxis remains a common chief complaint in the ED. The management of epistaxis is highly variable, with a wide range of packing implements and hemostatic agents currently available. In one survey of otolaryngologists in England and Wales, over three-fourths of patients admitted to the hospital for epistaxis required nasal packing, with anterior packing employed in the vast majority of these cases (Kotecha 1996). While the use of nasal packing has likely decreased since this study’s publication, and is likely much lower when considering all patients presenting to the ED, anterior packing remains a common procedure for emergency physicians.
The role of prophylactic systemic antibiotics when anterior nasal packing is employed remains highly controversial. The authors of the American College of Emergency Physician’s Focus on Treatment of Epistaxis note that while direct evidence is lacking, “most sources recommend TMP/SMX, cephalexin, or amoxicillin/clavulanic acid to prevent sinusitis and toxic shock syndrome [TSS].” While the prevention of toxic shock syndrome is often cited as a reason for prescribing antibiotics in these cases, this serious complication is exceedingly rare. The incidence of TSS following nasal surgery is approximately 16.5 in 100,000, or 1 in approximately 6000 cases. While the exact incidence of TSS following anterior nasal packing in epistaxis is unknown, no cases have been reported in the literature. Of 61 cases of TSS identified in the Minneapolis-St. Paul area between 2000 and 2006, none were attributed to an upper respiratory source (Devries 2011).
A survey of physicians in the United Kingdom conducted in 2005 revealed that 78% of interviewees believed that the use of prophylactic antibiotics with anterior nasal packing reduced the incidence of infection (Biswas 2006). There is, however, limited evidence regarding the effect of antibiotics on the infectious complications of packing. One large randomized trial evaluating the use of prophylactic antibiotics with nasal packing following septoplasty found no difference in post-operative pain, infectious symptoms, or the amount of purulent nasal discharge with or without prophylactic antibiotics (Ricci 2012). These results support the findings of a previous systematic review of post-operative nasal surgery patients (Georgiou 2008); however, their applicability to patients with anterior nasal packing for epistaxis is unclear. While differences in packing location (anterior vs. posterior), sterility of the environment (operative room vs. ED), and the nasal cavity itself (post-surgical vs. non-instrumented) may have some effect on the incidence of infectious outcomes, it seems reasonable to extrapolate these results to our patient population.
Unfortunately, no randomized controlled trials evaluating the effect of antibiotics on outcomes following epistaxis could be identified. What evidence does exist, however, suggests that antibiotics are unnecessary and potentially harmful. Anterior nasal packing and antibiotic administration have been found to have no effect on the microbiological flora of the nasal cavity following epistaxis (Biswas 2009). Two before and after studies evaluating changes in protocol, with a move away from the use of routine prophylactic antibiotics, also found that antibiotics had no affect on more clinically important patient outcomes. The first of these studies (Pepper 2012) enrolled 159 patients, of whom approximately half were treated with prophylactic amoxicillin-clavulanic acid or clarithromycin while the other half received no antibiotics. No infectious complications (sinusitis, otitis media, or TSS) were identified in either group. In the latter study (Biggs 2013), 38 patients were enrolled prior to the implementation of a protocol to reduce antibiotic use, while 19 patients were enrolled following implementation. The rate of antibiotic use was significantly reduced by the protocol, from 74% to 16%. The authors found no difference in infectious symptoms between the groups at 6-week telephone follow-up.
Unfortunately, none of these studies assessed adverse reactions to the antibiotics administered. Rates of serious adverse reactions to antibiotics can be difficult to estimate. One report estimates the rate of anaphylaxis from antibiotic administration to be around 1 in 5000, somewhat lower than the 1 in 6000 rate of TSS in nasal packing following nasal surgery. Assuming a similar rate of TSS following anterior packing in epistaxis, and assuming that antibiotics completely eliminated its occurrence, the benefit would still be outweighed by the risk of serious harm. While this analysis does not account for other infectious complications - such as sinusitis and otitis media - it also does not account for other serious complications of antibiotic use - such as Stevens-Johnson syndrome and Clostridium difficile infections - or other less serious adverse reactions - such as rash, diarrhea, nausea, and vomiting. Given the low reported incidence of sinusitis and otitis media in the literature following nasal packing, it seems highly likely that the risks of antibiotic administration would outweigh the benefits when all complications are considered. Unfortunately, the rarity of both infectious and drug-related complications mean that large sample sizes would be required to definitively demonstrate the superiority of either treatment option, and such a study seems unlikely to occur in the near future.
The current literature on this topic is unfortunately lacking in both methodology and sample size, and it is difficult to make firm conclusions. This conundrum is common, and the typical question remains: “What amount of evidence is required to change our practice?” Given that our “standard of care” is to administer prophylactic antibiotics when we place anterior packing in the ED, and that this is frequently the recommendation of our ENT consultants, some would argue that rigorous evidence is needed before we can safely advocate for a change in practice. In the parlance of our legal system, we would need to prove “beyond a reasonable doubt” that the risks of antibiotic administration outweigh the benefits. I would instead argue that a civil (rather than criminal) burden of proof applies, and that we need merely prove our case “by a preponderance of the evidence.” As is often the case, our current practice and our colleagues’ usual recommendations are based on anecdote and dogma, rather than on sound research and data. Given the very real potential for harm with unnecessary antibiotic administration, the current body of evidence simply does not support the routine administration of prophylactic antibiotics following anterior nasal packing in epistaxis.
Subcutaneous Insulin in the Treatment of DKA
May 07, 2014
Show notes
Journal Club Podcast #13: April 2014
Dr. Chandra Aubin and I discuss subcutaneous fast-acting insulin as an alternative to insulin drips in the treatment of diabetic ketoacidosis...
One afternoon you are working in your emergency department (ED) and walk in to see a new patient. Mr. X is a 24 year-old with a history of type I diabetes who presents with a complaint of weakness. He reports to you that one month ago he lost his job and hence lost his insurance. He has been unable to afford his insulin or syringes and was trying to “stretch them out” by only using one injection per day. He ran out completely 3 days prior to arrival, and in the interim developed polyuria and polydipsia, followed by nausea, vomiting, and generalized weakness. He denies any infectious symptom, abdominal pain, chest pain, or shortness of breath, though he does appear mildly tachypneic. He is also mildly tachycardic, but otherwise afebrile and hemodynamically stable. His exam is unremarkable.
His blood sugar is checked at the bedside and is 540 mg/dL, and his finger-stick ketones are 4.3 mmol/L. You start by giving him a liter of normal saline (NS) while you await his chemistry labs, but you’re pretty sure he’s in diabetic ketoacidosis (DKA). His labs come back as follows: Na 131, K 4.1, Cl 100, CO2 13, and his anion gap is 22. You realize that you will need to treat his DKA, but are also aware that all of your ICU beds are full, and that you cannot send a patient to the floor on an insulin drip. The patient is also begging you to keep the cost of his care to a minimum, since he has no insurance at the moment. Given the availability of fast-acting insulin analogs (lispro and aspart) you wonder if there is any place for subcutaneous (SC) fast-acting insulin, as an alternative to a continuous infusion of intravenous (IV) regular insulin, in the management of mild to moderate DKA. You decide to do a brief search of PubMed to see if this is even a reasonable question…
PICO Question:
Population: Patients (adult or pediatric) with mild to moderate DKA.
Intervention: Subcutaneous fast-acting insulin analog (aspart or lispro)
Comparison: Continuous infusion of intravenous regular insulin.
Outcome: Duration of therapy, ICU admission, ICU length of stay, hospital length of stay, hypoglycemia, recurrence of DKA.
Search Strategy:
You use the PubMed advanced search builder to create the following search strategy: (aspart OR lispro) AND ((diabetic ketoacidosis) OR DKA) (http://tinyurl.com/q4neutu). This identifies 38 articles, from which the following 4 most relevant articles are chosen.
Bottom Line:
DKA is a relatively common and dangerous complication of diabetes in both children and adults, with an estimated mortality of around 13%. In 2009, seven of every 1000 diabetics were admitted to the hospital for DKA. The primary treatment is hydration, electrolyte monitoring, and insulin therapy, traditionally accomplished via IV regular insulin,. Both the American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD) recommend a continuous infusion of IV regular insulin as standard of care in the management of DKA. These recommendations are based primarily on studies from the 1970s (Menzel 1970, Fisher 1977) that suggested that the delayed onset and longer half-life of SC and IM regular insulin make these routes inadequate for the management of DKA. However, these studies evaluated the use of regular insulin, and pre-dated the development of fast-acting insulin analogs (aspart and lispro), which may be more efficacious in the management of DKA when administered by these alternate routes. Insulin lispro, for example, has an onset of action of 10 to 20 minutes and reaches peak concentration within 30-90 minutes when administered by SC injection (Holleman 1997).
Management of DKA with continuous IV insulin is typically accomplished in an ICU or intermediate-care setting. As the population ages, the demand for ICU beds is increasing, and availability is often limited. ICU admissions also drastically increase the cost of care. While patients in DKA are often critically ill, their care is generally algorithmic, and may not require ICU level care in those without severe DKA. Given that ICU care is often dictated by the use s continuous IV infusion of insulin, an alternative regimen that involves intermittent SC insulin may allow admission to general medical wards or “step-down” units.
The current body of literature comparing IV and SC insulin in DKA is comprised of small, randomized trials (Umpierrez 2004, Umpierrez 2004, Della Manna 2005, Karoli 2011). The outcomes from these studies suggest that the use of SC fast-acting insulin is both safe and effective at treating mild to moderate DKA. No differences were observed in the duration of therapy required to resolve hyperglycemia or DKA. The incidence of hypoglycemia was low in the all of the studies and similar with either treatment. There were no episodes of recurrent DKA or death were in any of the studies. In adults, an initial SC injection of 0.3 units/kg of insulin aspart or lispro can be given, followed by SC injections either hourly (0.1 units/kg) or every 2 hours (0.2 units/kg). In pediatric patients, it is reasonable to forego the initial bolus, and instead administer 0.15 units/kg every 2 hours.
While these regimens seems to be safe and effective, their benefit over traditional IV strategies is less clear. The primary potential benefit involves eliminating the need for ICU admission, and thereby reducing cost. Only one of these studies assessed the cost of care, and indicated a 39% reduction with subcutaneous insulin(Umpierrez 2004). However, it is quite possible that this cost difference was due to added ICU charges rather than a true difference in the intensity of care required (Haas 2004). Patients receiving SC insulin had blood glucose levels checked every hour, while levels in those receiving IV insulin were only checked every 2 hours. Given the frequency of insulin administration required with a SC strategy - every 1 to 2 hours - the amount of nursing time required may actually increase with SC insulin. If the use of SC insulin does not reduce ICU admissions, then there is no benefit, and IV regular insulin remains a logical treatment option. In a retrospective chart review of DKA patients treated with SC aspart at Rush University Medical Center in Chicago, there was still a mean ICU length of stay of 43.36 hours, indicating that such patients were still admitted to the ICU for initial management.
Perhaps, then, we should alter our question, and instead be asking whether patients with uncomplicated DKA be admitted to the ICU at all, regardless of the route of insulin administration chosen? A review of 67 cases of DKA admitted to the ICU at Truman Medical Center in Kansas City, MO found that over a third of patients did not warrant ICU treatment based on existing admission criteria. These data suggest that increased use of “step-down” or intermediate care units could reduce the need for ICU admission in uncomplicated DKA patients, whether IV or SC insulin strategies are employed.
Biomarkers (Procalcitonin) to Diagnose Sepsis
Mar 31, 2014
Show notes
Journal Club Podcast #12: March 2014
I'm joined by Drs. Larry Lewis and Matt Dettmer to talk about using biomarkers, specifically procalcitonin, to diagnose sepsis...
You are rotating at a hospital just outside of Honolulu, HI. A patient presents from dialysis with nausea and vomiting. The patient has been feeling unwell for several days, presented to dialysis and had several episodes of non-bloody emesis. Their dialysis session was completed and then the patient was transferred to the ED for further evaluation. The patient denies abdominal pain and respiratory symptoms. The patient is afebrile, tachycardic with a heart rate in the 120s, a blood pressure of 95/65, mildly tachypneic with a respiratory rate of 22, saturating 98% on room air. On exam, the patient appears to have dry mucous membranes, clear lungs, soft abdomen. The patient has an in-dwelling right IJ dialysis catheter; the site is appropriately dressed, appears clean and dry and has no surrounding erythema.
Basic work-up is started and the patient has a clear chest X-ray, mild leukocytosis of 13,000, EKG showing sinus tachycardia. Creatinine is elevated to 5, other electrolytes are within normal limits. Point of care lactate is mildly elevated at 2.5. After a small bolus of IV fluids, the patient remains tachycardic with a soft blood pressure. You consider the possibility that the patient may be septic and consider the initiation of broad spectrum antibiotics.
Since your medical license hasn’t been processed, you cannot actively participate in the care of this patient. Nevertheless, your medical curiosity is piqued and you leap to a computer and begin a literature search to see if there is a role for biomarkers to help determine whether this patient would benefit from antibiotics. You develop the following PICO and begin your journey down the rabbit hole.
PICO Question:
Population: Adult patients presenting to the Emergency Department meeting SIRS criteria without clear source of infection.
Intervention: Use of procalcitonin to identify patients with bacterial sepsis
Comparison: Standard management
Outcome: Diagnosis of sepsis due to bacterial infection
Search Strategy:
You access PubMed and search the Clinical Queries tool using the terms "procalcitonin AND sepsis" with the narrow filter applied (http://tinyurl.com/pya5gs7). This results in 261 articles, from which you choose the following four, including recent meta-analysis on the topic.
Bottom Line:
Sepsis is defined as the presence of a systemic inflammatory response syndrome (SIRS) in the presence of an infectious etiology. Sepsis is often thought of as the result of a severe infection, resulting in a systemic inflammatory response syndrome (Stearns-Kurosawa 2011). In reality, sepsis represents a clinical spectrum of disease, ranging from a relatively mild immune response to devastating global systemic inflammation leading to vasodilation, hypoperfusion, and multi-organ system failure (Odeh 1996).
While patients on the milder end of the spectrum frequently fare well, mortality in those with severe sepsis and septic shock approached 50% in the late 1990’s (Rivers 2001). Even with the advent of early-goal directed therapy, and an increased recognition of the severity of these illnesses and need for timely intervention, mortality remained between 30 and 40% in the following decade(Ferrer 2008, Levy 2010, Castellanos-Ortega 2010). More recent evidence from the newly published ProCESS trial suggests that mortality is now closer to 20%, though this study was performed in academic centers in the US, and some are concerned that a Hawthorne effect may have contributed to this low mortality.
Regardless of the exact cause of this decreased mortality, it seems likely that earlier recognition of disease and initiation of aggressive management has led to improved outcomes in these sicker patients. For example, research has demonstrated decreased mortality associated with earlier administration of antibiotics (Gaieski 2010) and larger volume of fluid administered in the initial 3 hours (Lee 2012). Early diagnosis of sepsis, and differentiation from SIRS due to a non-infectious etiology is therefore critical in the management of these patients.
Early differentiation would benefit not only those patients with severe sepsis and septic shock, but could also improve outcomes in those ultimately diagnosis with a non-infectious etiology. In one study of severe non-infectious SIRS in the ICU, mortality was found to be similar to that in severe sepsis (Dulhunty 2008). While a large proportion of cases identified were either post-operative or trauma-related, and may be more easily differentiated from severe sepsis, many were due to underlying cardiovascular, pulmonary, GI, and neurologic conditions. Diagnosing such patients with severe sepsis, and treating them as such initially, has the potential to delay diagnosis and definitive treatment of the true underlying etiology. Additionally, the administration of broad-spectrum antibiotics in such cases would be of no therapeutic benefit, and may in fact be harmful. Data from the CDC indicate that the use of antibiotics confer a relative risk of developing of a C. difficile infection of 3.1 (95% CI 2.5 to 3.8), and suggest that a 30% decrease in the use of broad-spectrum antibiotics would reduce C. difficile infection rates by 26%.
Unfortunately, the differentiation of sepsis from non-infectious SIRS can be difficult, particularly in the early phase of the disease. As a result, several biomarkers, most notably procalcitonin, have been proposed as a means of making this differentiation. Procalcitonin is the peptide precursor of calcitonin. Its production is stimulated by endotoxins and cytokines, and is inhibited by interferon-gamma, a cytokine produced by viral infections. As a result, procalcitonin has been proposed as a means of differentiating bacterial infections from both viral infections and non-infectious pro-inflammatory conditions (Delevaux 2003).
We identified 4 articles looking at the use of procalcitonin specifically to distinguish sepsis from SIRS of non-infectious etiology. Three of the studies involved primary research conducted on Emergency Department (ED) patients (Tsalik 2012, Jaimes 2013, Loonen 2014), while the fourth was a systematic review and meta-analysis (Wacker 2013). Sensitivities were poor in the primary studies, ranging from 55% to 68%; specificity fared only slightly better, as low as 64% in one study, and as high as 97% when a higher cut-off was used (sacrificing sensitivity, which decreased to 18%). The sensitivity and specificity in the meta-analysis were 77% and 79%. The resulting likelihood ratios, reported in Table 1, indicate that the probability of sepsis changes very little with procalcitonin results. Some have suggested that while procalcitonin alone cannot differentiate noninfectious SIRS from sepsis, it can be used in conjunction with additional clinical information to aid in diagnosis and management. Unfortunately, such a role has not been well-defined, and no clinical decision rules involving procalcitonin have been developed to assist in sepsis diagnosis. If procalcitonin is to become a relevant aspect of sepsis care, additional research will need to identify a particular clinical role with an improvement in patient-oriented outcomes.
The meta-analysis we reviewed unfortunately suffered from a large degree of heterogeneity. Clinically, the included studies were conducted in a variety of settings, including pediatric, medical, and surgical ICUs, hospital wards, and the ED. Additionally, the studies evaluated procalcitonin using a wide range of cut-offs, 0.1 to 15.75 ng/mL, making interpretation of the reported test characteristics difficult.
Study
Cut-off
AUC
(95% CI)
LR+
LR-
Jaimes
0.3 ng/mL
0.69 (0.65-0.72)
1.77
0.57
Tsalik
0.1 ng/mL
0.5 ng/mL
3 ng/mL
0.72
(N/A)
1.9
3.2
6.3
0.51
0.68
0.84
Loonen
(2 ng/mL)
0.81 (0.70-0.91)
3.9
0.52
Wacker
various
0.85 (0.81-0.88)
3.7
0.29
The result was a high degree of reported statistical heterogeneity, with an I2 of nearly 78% for both sensitivity and specificity, and 96% for the bivariate model. Given this high degree of heterogeneity, it would have made more sense for the authors to report the data of the individual studies without performing a meta- analysis.
Unfortunately, sepsis research in general is handicapped by the lack of a gold standard. Reliance on source testing and culture results leads to high false negative rates, as blood cultures are positive in only around one-fourth of septic patients (Bates 1997). Diagnostic research on sepsis therefore relies on expert opinion and consensus to differentiate septic from non-septic patients. While there are methods to attempt to correct for the absence of a true gold standard (Reitsma 2009, Rutjes 2007), including the use of panel consensus as employed in our studies, these methods are lacking in methodological research. Despite the moderate to high rates of agreement noted in the studies by Jaimes and Tsalik (65% and 82%, respectively), this reference standard is far from perfect. Evaluation of the diagnostic accuracy of a test depends on how well the results of the test in question agree with outcomes based on the gold standard. When the reference standard is imperfect, the resulting test characteristics (sensitivity, specificity, likelihood ratios) are less reliable.
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