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.


Hyperglycemia management in the ICU

“Intensive versus conventional glucose control in critically ill patients.” – the NICE-SUGAR investigators, The New England Journal of Medicine, March 26th, 2009

“Intensive insulin therapy in critically ill patients.” – Greet van de Berghe et al., The New England Journal of Medicine, November 8, 2001

“Intensive insulin therapy in the medical ICU.” – Greet van de Berghe et al., The New England Journal of Medicine, February 2, 2006


Control of blood glucose in the Intensive Care Unit (ICU) and the hospital has implications in many disease processes, including cardiovascular, renal, and infectious problems. Elevated or abnormally low blood glucose values can compound with the primary problem and complicate a patient’s hospital stay. Over the course of the 2000s, three large studies attempted to establish and validate a strategy to control blood sugar in the ICU.

The first two trials (van de Berge 2001 and van de Berghe 2006) were conducted at a single center with patient numbers in the 1400-1500 range. The 2001 study followed patients in the Surgical ICU, and the 2006 study in the Medical ICU. These investigators proposed an intensive glucose control regimen where an insulin infusion was initiated at levels higher than 110 mg/dL (the upper limit of normal blood sugars) and titrated to blood levels in the 80-110 mg/dL normoglycemic range. This was compared with a conventionally treated group where insulin drips were started once blood sugar exceeded 215 mg/dL, and titrated to a range of 180-215 mg/dL.

The NICE-SUGAR study was a multi-centered study that included medical and surgical ICUs, with a total patient population of 6104. The intensive therapy was repeated similar to the studies above. The conventional arm of patients received an insulin drip once blood glucose levels exceeded 180 mg/dL. Insulin drip was discontinued when glucose levels fell below 144 mg/dL. The target glucose level was < 180 mg/dL. Importantly, inclusion criteria for this trial selected patients that expected to remain in the ICU > 3 days.


Van de Berghe 2001 found that the intensive therapy resulted in reduced in-hospital mortality and ICU mortality, especially in patients staying longer that 5 days. The intensive therapy group also had fewer morbidity rates including lower rates of sepsis. Hypoglycemia did occur more frequently in the intensive therapy group.

Van de Berghe 2006 also found ICU and in-hospital death was lower in the intensive treatment arm in patients who stayed in the ICU for longer than 3 days. There was no significance in mortality between the two arms in terms of in-hospital or ICU mortality for all ICU patients. Hypoglycemia occurred more frequently in the intensive therapy arm. There was an improvement in morbidities – requirements of mechanical ventilation, ICU stay and hospital stay in the intensive arm, but no significant fewer episodes of sepsis.

The NICE-SUGAR study found an increased all-cause mortality at 90 days after admission to the ICU in the intensive treatment arm when compared to conventional treatment. The majority of the deaths in both arms of the study were in-hospital or in the ICU. There was no significant difference in morbidities, including sepsis, except for an increased number of hypoglycemic episodes in the intensive glucose management group.

Why We Do What We Do

After the 2001 van de Berghe paper, intensive glucose management became the standard of practice in the ICU. However, after the striking results of the NICE-SUGAR study, the recommended practice is now a liberal approach to glucose management with a goal of blood sugars < 180 mg/dL and treatment only above this level. Large sample size and diversity in multiple trial centers provide this study with validity in a broad range of ICU and hospital applications.

Statistical significance of the data is also important – the 2006 medical ICU van de Berghe study failed to find a difference between in-hospital and ICU mortality between the two arms of the study for all patients, so the contemporary standard of practice (intensive management) was considered to be safe and valid. However, NICE-SUGAR’s results were statistically significant in showing that intensive therapy actually led to increased mortality. Clinical practice changed quickly as a result of this significant data.

After the results of the NICE-SUGAR study, there was extensive discussion into why intensive glucose control increased mortality, in stark contrast to the previous two landmark studies by van de Berghe. The authors of NICE-SUGAR did not expand on a cause for the increased mortality, but referred to lower blood sugars, increased insulin administration and increased episodes of hypoglycemia as being possible explanations. When under stress, as critical patients are, the body naturally produces a hyperglycemic state with increased corticosteroid responses, and dampening this response with artificial insulin administration may work against the complex defense mechanisms of the stressed-state body. The results of NICE-SUGAR interestingly correlate with another landmark trial on outpatient diabetes, the ACCORD trial, which also found that intensive glucose management increased mortality. However, more research was requested by both the ACCORD and NICE-SUGAR studies to explain their results.

1. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, Blair D, Foster
D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hébert PC, Heritier S,
Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J,
Robinson BG, Ronco JJ. Intensive versus conventional glucose control in
critically ill patients. N Engl J Med. 2009 Mar 26;360(13):1283-97. doi:
10.1056/NEJMoa0810625. Epub 2009 Mar 24. PubMed PMID: 19318384.

2. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M,
Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in
critically ill patients. N Engl J Med. 2001 Nov 8;345(19):1359-67. PubMed PMID:

3. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I,
Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin therapy in the
medical ICU. N Engl J Med. 2006 Feb 2;354(5):449-61. PubMed PMID: 16452557.

Statins: Game Changers in CVD

In a recent post we had discussed the use of aspirin in the setting of an acute MI. Our second look at landmark trials examining the treatment of coronary vascular disease (CVD) focuses on primary prevention of CVD. Elevated cholesterol levels have long been implicated in the progression of CVD, and numerous medications have been developed to reduce plasma cholesterol levels as a means to reduce the incidence of myocardial infarctions and other cardiovascular events. In fact, the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) revealed that the CVD risk reduction was proportional to the reduction in LDL cholesterol. Through the 1980s, fibrates and bile acid resins (cholestyramine) were in use, and studies from multiple institutions had demonstrated their ability to moderately reduce cholesterol levels. Used alone, neither cholestyramine nor the fibrates could achieve greater than a 10-15% reduction in LDL. The most promising development was the approval of HMG-CoA reductase inhibitors, otherwise known as statins. Several smaller studies suggested an improvement in plasma cholesterol levels and cardiovascular outcomes with statin therapy. The Scandinavian Simvastatin Survival Study (4S) assessed the effect of simvastatin on total mortality and cardiovascular outcomes and confidently addressed the question.

Between 1988 and 1994, 4444 patients between the ages of 35 and 70 were randomly assigned to receive various doses of simvastatin or placebo. Dosing was titrated to a specific serum cholesterol value; patients who were above this value received up to 40mg per day, and those below this value were titrated down. The study group was followed for an average of 5.4 years. The primary endpoint for 4S was total mortality – an important distinction since a few research trials with fibrates, including one from the WHO, had shown an increase in non-cardiovascular deaths. Randomization was successful in evenly dividing patients already on multiple medications for hypertension, angina and diabetes. A similar study conducted at the same time in Scotland, the WOSCOP study, was looking at the effect of pravastatin on primary prevention. While 4S was not as straightforward as WOSCOPS, it was far more generalizable in a number of ways. For one, it included women. Other aspects of the study that stand out are the broader age range, existing CVD or diabetes and a percentage of smokers closer to that of the US.

The data from 4S were impressive. Patients on simvastatin on average saw a 35% decrease in LDL cholesterol. More importantly, this decrease correlated with a relative risk of death of 0.70 when compared to placebo (182 vs 256 deaths). This reduction in deaths was attributable to a 42% decrease in cardiovascular mortality. Likewise, simvastatin also lead to a pronounced decrease in non-fatal cardiovascular events (RR 0.66). Adverse effects were few – 1 episode of rhabdomyolysis in the simvastatin group. Complaints of myalgias and elevations in LFTs were similar between placebo and simvastatin.

Prior to this study, the benefits of lipid-lowering therapy lacked a consensus. The 4S trial conclusively determined that statin therapy was a safe and more effective treatment choice in lowering serum LDL cholesterol than other lipid-lowering agents. Moreover, it provided the largest reduction in cardiovascular mortalities, and the benefit was witnessed in all age groups. Today many newer variations of statins exist but simvastatin continues to be the first line therapy for many of our patients.


The Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994. 344:1383-1389.