PIOPED II: Assessing CTAs in PE diagnosis

Pulmonary embolism (PE) is the blockage of arteries that perfuse the lungs, generally due to clots. Rapid assessment and initiation of anti-coagulation in suspected PE cases is paramount as the risk of recurrent PE in confirmed cases could be as high as 25% within the first 24 hours. Fortunately, diagnosis and management of pulmonary embolism quickly improved at the turn of the 21st century. Between 1995 and 2001, Wells et al developed criteria to assess the likelihood of a pulmonary embolism based on the clinical presentation. At the same time, a new development in computed tomography (CT), termed spiral CT, permitted visualization of pulmonary vasculature. The Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) study addressed the benefits of CTA.

One issue when attempting to assess the accuracy and usefulness of a new imaging modality is having a strong gold standard with which to compare. Given that the existing gold standard for PE is a pulmonary angiography or digital subtraction pulmonary angiography (DSPA) – a highly invasive, time-consuming study that uses direct arterial catheter access for contrast-enhanced imaging – an alternative method was needed. Using multiple ancillary tests, the authors employed a composite reference diagnosis as a gold standard in addition to DSPA. A diagnosis of PE was given when ventilation-perfusion (V/Q) scanning showed high probability in a patient without a history of PE or when V/Q scans showed moderate probability with positive lower extremity venous ultrasonography. PE was ruled out with low pre-test probability and negative results from V/Q scans or venous ultrasonography. Using these standards, 632 patients were ruled out for PE. 592 received a CT-PA and were followed for 6 months. Of that group, only 2 required anticoagulation, indicating that the composite reference diagnosis was a suitable substitute in situations where DSPA was not necessary.

The results, while impressive on their own, are more indicative when compared to the results from the first PIOPED study, which examined V/Q scans. In the original study, V/Q scans achieved 98% sensitivity but very poor specificity (10%). In contrast, CTA achieved 83% sensitivity and 96% specificity. When venous angiography was included (CTA-CTV), sensitivity improved to 92%. CTA also inherently provided imaging of the whole chest and upper neck, which in certain cases produced alternative diagnoses.

The results of PIOPED II demonstrate that, when used in conjunction with modified Wells criteria, CTA provides high positive and negative predictive values for PE. Effectively, concordant clinical assessment and imaging results can rule-in or rule-out a diagnosis which was not possible with V/Q scans alone. In patients with suspected PE and who do not have contraindications for IV contrast, it offers a shorter clinical algorithm for diagnosis and management by eliminating the uncertainty of moderate probability V/Q scans. Today CTA has become a second gold standard in the diagnosis of PE due to the invasiveness of pulmonary angiograms. Nevertheless, in both algorithms, any inconclusive results must be followed up by DSPA or serial lower extremity ultrasounds. As the authors themselves admit, the benefits of CTA-CTV are largely dependent on the expertise of the radiology staff reading the film. For institutions with this capability, the diagnosis and management of PE is greatly improved with CTA.

 

Multidetector computed tomography for acute pulmonary embolism. Stein PD, Fowler SE, Goodman LR, et al. N Engl J Med. 2006. Jun 1;354(22):2317-27.

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Surviving Sepsis

“Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock” – Emanuel Rivers et al., The New England Journal of Medicine, November 8, 2001

Introduction

Sepsis and septic shock are common conditions associated with high mortality, and the incidence and mortality continue to rise [1,2]. Sepsis is defined as a systemic inflammatory response with deteriorating hemodynamic parameters, most often due to disseminated infection, and septic shock occurs when the blood, oxygen and nutrient supply is so compromised that it causes multi-organ failure. Sepsis is an acute problem, characterized by rapid onset and deterioration, and treatment is time sensitive. Antibiotics are the mainstay of therapy, as they will eliminate the offending microbes, but supportive care to maintain organ function is crucial in reducing mortality.

The investigators of this study proposed an early (within the first 72 hrs) goal-directed treatment schedule for this supportive care. They outlined parameters to measure organ perfusion with goals for therapy – central venous pressures (goal 8-12 mmHg), central venous oxygen content (goal > 70%) and arterial pressures (goal 65-90 mmHg). To meet these goals, they administered fluids, blood, vasopressors, vasodilators and inotropes. This therapy regimen was compared with standard therapy at clinicians’ discretion. The outcomes measured were organ dysfunction by APACHEII scores, MODS scores,arterial pH and serum lactate levels and 28 and 60-day all cause mortality.

Results

During the first 72 hours, central venous oxygen saturation goals were achieved in ~60% of standard therapy patients and ~95% of goal directed therapy patients. Hemodynamic parameters (arterial pressures, central venous pressures) were at goal in 86% of standard therapy patients and 99% of goal directed therapy patients. Patients in the goal directed arm had higher blood pressures and higher central venous oxygen saturations during the entire 72 hours. Goal directed therapy patients received more fluids, more blood and more inotropes within the first 6 hours of therapy, but required less fluids, less blood and less vasopressors after that (hours 7-72).

APACHE II and MODS scores of organ dysfunction were lower in patients in the goal directed group during hours 7-72. Base deficit was lower, serum lactate was lower and arterial pH was higher during the same time period. Twenty-eight day and 60-day mortality figures were lower in the goal directed group, which was mainly the result of in-hospital mortality.

Why We Do What We Do

Treatment and management of sepsis is highly dependent on early therapy. As illustrated in this trial, aggressive fluid, blood and inotropic resuscitation in the first 6 hours can have profound impact on further treatment requirements and organ dysfunction in the following 3 days, as well as in-hospital mortality. Early recognition is also key to initiating therapy during the period where it is most helpful. Increased volume and blood administration outside the first 6 hours did not result in improved organ function or mortality. Directing therapy towards specific hemodynamic goals standardizes practice and gives clinicians strong guidelines to treat towards. Therefore, the benefits of placing invasive central venous and arterial lines outweigh the complications of these procedures.

Organ perfusion in septic shock is a simple physiologic system that must be aggressively managed early on to improve patient outcomes. Even though cardiac output and vascular permeability might be severely limited, administration of fluid and blood to carry oxygen and nutrients can support the body during the critical period of the disease. As clinicians, we must all learn to recognize sepsis early and target therapy to hemodynamic goals to provide the best outcome for our patients in such a dangerous and common disease.

References

1. Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid increase in
hospitalization and mortality rates for severe sepsis in the United States: a
trend analysis from 1993 to 2003. Crit Care Med. 2007 May;35(5):1244-50. PubMed
PMID: 17414736.

2. Melamed A, Sorvillo FJ. The burden of sepsis-associated mortality in the
United States from 1999 to 2005: an analysis of multiple-cause-of-death data.
Crit Care. 2009;13(1):R28. doi: 10.1186/cc7733. Epub 2009 Feb 27. PubMed PMID:
19250547; PubMed Central PMCID: PMC2688146.

3. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E,
Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early
goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl
J Med. 2001 Nov 8;345(19):1368-77. PubMed PMID: 11794169.

Ranson’s Criteria: For the History Books

Acute pancreatitis – a common indication for hospitalization in the US – is a feared complication of alcohol use, gallstones, abdominal trauma, steroids, mumps, high fat and calcium level, ERCPs and even scorpion stings. Up to 25% of patients with acute pancreatitis will develop severe acute pancreatitis. It’s a tricky clinical situation to manage due to the difficulty in estimating the severity of the disease; yet distinguishing between the two is critical as mortality rates are 1-2% for mild pancreatitis and up to 17% for severe cases. Prior to this study, physicians relied purely on clinical judgment to triage patients to the floor or the ICU, a method known to underestimate the severity of the disease. Ranson et al provided 11 criteria – 5 assessed at admission and the other 6 at 48 hours – to help predict the most severe cases, with the goal of aggressively treating these patients in the ICU or the OR.

The study suffered from many shortcomings, which complicated data analysis. The data itself was likely skewed due to selection and observer bias, the number of patients enrolled, and the variety of treatment methods employed. For example, 21 patients underwent abdominal exploration within 7 days of admission. Another 10 patients were randomized to early operative or non-operative management. Of those, all but one spent at least 8 days in the ICU. An additional category was non-randomized early management where 17 patients were managed by early operation within 48 hours of diagnosis. Operations varied widely, but the existing standard “recommended early laparotomy with cholecystostomy, gastrostomy, [jejunostomy] and pancreatic drainage in patients with severe acute pancreatitis”. With all these variables, it becomes impossible to assess outcomes based on the various treatment modalities employed – the power in each group and for the whole study is greatly reduced. Nonetheless some of the conclusions regarding blood loss and fluid depletion were accurate. Importantly, the authors noted that a worsening BUN in the face of aggressive fluid replacement was a more sensitive index for survival than the BUN at admission.

At the time, the 11 criteria now known as Ranson’s Criteria were the best available for predicting severity. However, more recent studies have demonstrated that Ranson’s criteria as an aggregate are a relatively poor predictor of disease severity. Today we have at our disposal a number of scoring systems that have been shown to be better prognosticators than Ranson’s Criteria. One, the APACHE II scoring, was developed for critically ill ICU patients. Modern guidelines from the American Gastroenterology Association recommend using the APACHE II scoring system because of its good negative predictive value for severe acute pancreatitis. Still, it continues to be difficult to accurately predict outcomes and severity, although early aggressive management and the use of other diagnostic modalities not available to the authors at the time have improved survival.

The complexity of the interactions of numerous risk factors that ultimately lead to an attack of acute pancreatitis almost precludes having a simple scoring system. It seems that Ranson’s criteria are best used during hospital rounds where medical students and residents can rapidly regurgitate them. It is our hope that they recognize this study for its historic value and instead employ APACHE II to guide early management.

Ranson JH, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC. Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet. 1974; 139:69.

(Unfortunately there isn’t even an abstract of the original article available online. For those at UTSW, I can e-mail you a photocopy of the article since it isn’t available online through the library)

ISIS-2: Managing an Acute MI

Got chest pain? Then pop some aspirin and head to the ER. This was, in a nutshell, the conclusion of the Second International Study of Infarct Survival (ISIS-2). 1.5 million Americans suffer from a heart attack every year and many are treated in the ER with morphine, oxygen, nitrates, aspirin and beta-blockers. Some are taken to the cath lab. Part of this methodical management stems from the results of ISIS-2. Prior to ISIS-2, there was exactly one trial that examined the use of aspirin, an anti-platelet agent, acutely during a myocardial infarction (MI). (In that study, one dose of aspirin was given for a suspected MI, and mortality was assessed at one month. The single dose conferred no mortality benefit and the authors concluded that aspirin was not beneficial in the acute setting.) The focus on streptokinase in ISIS-2 was less groundbreaking as there were a number of other concurrent trials studying the use of thrombolytic therapy for MIs. Still, in conjunction with other randomized clinical trials (GISSI, ISAM, etc), they quickly established a time frame of 3 hours for thrombolytic therapy, giving rise to the phrase “time is muscle”. Today, with rapid triage at the ED and improved times to percutaneous coronary intervention (PCI), we know it as 90 minutes for “door to balloon”.

The methodology in the study was consistent throughout the trial. Eligibility was made straight forward to encourage participation in various countries and ultimately 17,187 patients were recruited for the study. Patients were randomized for both aspirin and streptokinase. This created 4 distinct groups: streptokinase infusion, aspirin 160mg, streptokinase + aspirin, or placebo infusion and tablets. Participating physicians were encouraged to continue all other aspects of patient care as they saw fit, though they were required to report the intention to use any anticoagulation in addition to the trial medications. At the time of publication, discharge information on 204 patients (1.1%) was not available. Otherwise follow-up was strong, with 97% follow-up at 5 weeks after discharge and a median follow-up of 15 months.

Both 5-week mortality and 24-month mortality were analyzed. Aspirin afforded a 23% reduction in the odds of death when given within 24 hours of the onset of chest pain and continued for a month. This translates into 25 deaths avoided per 1000 patients treated (NNT of 40) and 15 non-fatal cardiovascular events avoided. This effect was further enhanced if aspirin was given within 4 hours of pain; mortality benefits were less pronounced if given after 4 hours. When examining both fatal and non-fatal events in the years following a myocardial infarction, the number needed to treat is far less than 40. This survival benefit was independent of the survival gains witnessed with streptokinase therapy. The combination of thrombolytic and anti-platelet therapy, administered within 4 hours of onset of chest pain, lead to a reduction of 40-50% in odds of death.

The administration of aspirin in the setting of an acute MI can substantially alter the outcome. Moreover, the gains in survival over the first few weeks persist well into the future with smaller amounts of daily aspirin. These benefits, definitively established by ISIS-2, cannot be understated. Simply put, for the 1.5 million MIs that occur in the US every year, taking a drug that is already found in nearly all households can prevent tens of thousands of deaths.

ISIS-2 Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988. Aug 13;2(8607):349-60.

(for those at UTSW, I can e-mail you a photocopy of the article since it isn’t available online through the library)