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Posts Tagged ‘C-reactive protein’

Accurate Identification and Treatment of Emergent Cardiac Events


Accurate Identification and Treatment of Emergent Cardiac Events

Author: Larry H Bernstein, MD, FCAP
In the immediately preceding article, I discussed the difficulties in predicting long-term safety for developing drugs, and the cost of failure in early identification.

It is not the same scale of issue as for the patient emergently presenting to the ED. Despite enormous efforts to reduce the development of and the complications of acute ischemia related cardiac events, the accurate diagnosis of the patient presenting to the emergency room is still, as always, reliant on clinical history, physical examination, effective use of the laboratory, and increasingly helpful imaging technology. The main issue that we have a consensus agreement that PLAQUE RUPTURE is not the only basis for a cardiac ischemic event. The introduction of  high sensitivity troponin tests has made it no less difficult after throwing out the receiver-operator characteristic curve (ROC) and assuming that any amount of cardiac troponin released from the heart is pathognomonic of an acute ischemic event.  This has resulted in a consensus agreement that

  • ctn measurement at a coefficient of variant (CV) measurement in excess of 2 Std dev of the upper limit of normal is a “red flag”
  • signaling AMI? or other cardiomyopathic disorder

This is the catch.  The ROC curve established AMI in ctn(s) that were accurate for NSTEMI – (and probably not needed with STEMI or new Q-wave, not previously seen) –

  1. ST-depression
  2. T-wave inversion
    • in the presence of other findings
    • suspicious for AMI

Wouldn’t it be nice if it was like seeing a robin on your lawn after a harsh winter?  Life isn’t like that.  When acute illness hits the patient may well present with ambiguous findings.   We are accustomed to relying on

  1. clinical history
  2. family history
  3. co-morbidities, eg., diabetes, obesity, limited activity?, diet?
    1. stroke and/or peripheral vascular disease
    2. hypertension and/or renal vascular disease
    3. aortic atherosclerosis or valvular heart disease
      • these are evidence, and they make up syndromic classes
  4. Electrocardiogram – 12 lead EKG (as above)
  5. Laboratory tests
    1. isoenzyme MB of creatine kinase (CK)… which declines after 12-18 hours
    2. isoenzyme-1 of LD if the time of appearance is > day-1 after initial symptoms (no longer used)
    3. cardiac troponin cTnI or cTnT
      • genome testing
      • advanced analysis of EKG

This may result in more consults for cardiologists, but it lays the ground for better evaluation of the patient, in the long run.  When you look at the amount of information that has to be presented to the physician, there is serious need for improvement in the electronic medical record to benefit the patient and the caregivers.  Recently, we have a publication on a new test that has been evaluated, closely related to the C-reactive protein (CRP), a test that has generated much discussion over the effect of treatment for patients who have elevated CRP in the absence of increased LDL cholesterol, diabetes, or obvious atherosclerotic comorbidities.  The serum pentraxin 3 test is related to cell mediated immunity, and an evaluation has been published in the Journal of Investigative Medicine.

Journal of Investigative Medicine Feb 2013; 61 (2): 278–285.
http://dx.doi.org/10.231/JIM.0b013e31827c2971

Serum Pentraxin 3 Levels Are Associated With the Complexity and Severity of Coronary Artery Disease in Patients With Stable Angina Pectoris
Karakas, Mehmet Fatih MD*; Buyukkaya, Eyup MD*; Kurt, Mustafa MD*; et al.
From the Departments of Cardiology and,Clinical Biochemistry, Mustafa Kemal University, Tayfur Ata Sokmen Medical School, Hatay, Turkey.
Reprints: Mehmet Fatih Karakas, MD, Antakya 31005, Turkey. E-mail: mfkarakas@hotmail.com.

Abstract
Background: Atherosclerosis is a complex inflammatory process. Although pentraxin 3 (PTX-3), a newly identified inflammatory marker, was associated with adverse outcomes in stable angina pectoris,

  • an association between PTX-3 and the complexity of coronary artery disease (CAD) has not been reported.

The aim of the present study is to assess

  • the association between the level of PTX-3 and
  • the complexity and severity of CAD assessed with
  • SYNTAX and Gensini scores in patients with stable angina pectoris.

Methods: The study population is 2 groups:

  • 161 patients with anginal symptoms and evidence of ischemia
    • who underwent coronary angiography and
  • 50 age- and sex- matched control subjects without evidence of ischemia .

Patients were grouped into 3 groups according to the complexity and severity of coronary lesions

  • assessed by the SYNTAX score (30 patients with a SYNTAX score of 0 were excluded).

Serum PTX-3 and high-sensitivity C-reactive protein (hs-CRP) levels were measured in both groups.

Results: The PTX-3 levels demonstrated

  • an increase from low to high SYNTAX groups (r = 0.72, P < 0.001).

Whereas the low SYNTAX group had statistically significantly higher PTX-3 levels when compared with the control group (0.50 ± 0.01 vs 0.24 ± 0.01 ng/mL, P < 0.001),

  • the hs-CRP levels were not different (0.81 ± 0.42 vs 0.86 ± 0.53 mg/dL, P = 0.96).
  • but  the intermediate SYNTAX group had higher hs-CRP levels compared with the low SYNTAX group (1.3 ± 0.66 vs 0.86 ± 0.53 mg/dL, P = 0.002).

Serum PTX-3 levels and hs-CRP levels were both correlated with the SYNTAX scores and Gensini scores (for SYNTAX: r = 0.87 [P < 0.001] and r = 0.36 [P = 0.01]; for Gensini: r = 0.75 [P < 0.001] and r = 0.27 [P = 0.002], respectively), and

  • according to the results of univariate and multivariate analyses, for “intermediate and high” SYNTAX scores, age, diabetes mellitus, low-density lipoprotein cholesterol, hs-CRP, and PTX-3
  • were found to be independent predictors, whereas
  • for the presence of “high” SYNTAX score only PTX-3 was found to be an independent predictor.
  • The receiver operating characteristic curve analysis further revealed that the PTX-3 level was
    • a strong indicator of high SYNTAX score with an area under the curve of 0.91 (95% confidence interval, 0.86–0.96).

Conclusions: Pentraxin 3, a novel inflammatory marker, was more tightly associated with the complexity and severity of CAD than hs-CRP and

    • it was found to be an independent predictor for high SYNTAX score.

The association between atherosclerosis and inflammation has been more understood during recent years. Currently, atherosclerosis is considered as a complex inflammatory process in which

    • leukocytes and inflammatory markers are involved.1

Several inflammatory markers

  1.  high-sensitivity C-reactive protein (hs-CRP),
  2. fibrinogen, and
  3. complement C3…. are associated with cardiovascular events.1–5

Pentraxin 3 (PTX-3), that resembles CRP both in structure and function,1 is produced both by

  • hematopoietic cells such as macrophages, dendritic cells, neutrophils, and by
  • nonhematopoietic cells such as fibroblasts and vascular endothelial cells.2

Plasma PTX-3 levels may be elevated in patients with

  1. vasculitis,6
  2. acute myocardial infarction,7,8 and
  3. systemic inflammation or sepsis,9
  4. psoriasis,
  5. unstable angina pectoris, and
  6. heart failure.10–13

Dubin et al14 reported that PTX-3 levels are associated with with adverse outcomes in stable angina pectoris (SAP). Despite reports about the association of PTX-3 and coronary artery disease (CAD),

an association between the level of PTX-3 and the complexity and severity of CAD is not established.15,16 Thus, the aim of this study was

  • to assess the association between the level of PTX-3 and the complexity and severity of CAD assessed with SYNTAX and Gensini scores in SAP patients.

MATERIALS AND METHODS

Of 211 patients were prospectively recruited,  161 SAP patients with evidence of ischemia (positive treadmill or myocardial perfusion scan) underwent coronary angiography for suspected CAD, and 50 age- and sex- matched outpatient subjects with a negative treadmill or myocardial perfusion scan test were taken as the control group. Patients were excluded if they had

  •  acute coronary syndrome
  • history of previous myocardial infarction;
  • coronary artery bypass grafting or percutaneous coronary intervention;
  • secondary hypertension (HT);
  • renal failure;
  • hepatic failure;
  • chronic obstructive lung disease and/or
  • manifest heart disease, such as
    • cardiac failure (left ventricular ejection fraction <50%),
    • atrial fibrillation, and
    • moderate to severe cardiac valve disease; and
    • SYNTAX score of zero

Similarly, patients were excluded with

  • infection,
  • acute stress, or chronic systemic inflammatory disease and
  • those who had been receiving medications affecting the number of leukocytes .

Thirty patients were excluded from the study because the coronary angiograms revealed normal coronary arteries (SYNTAX score of 0). All the participants included in the study were informed about the study, and they voluntarily consented to participate. The Serum PTX-3 level was measured on blood samples collected after 12-hour fast just prior to coronary angiography and kept at −80°C until the assays were performed. PTX3 was measured by enzyme immunoassay (EIA) using quantitative kit (human PTX-3/TSG-14 immunoassay, DPTX30; R&D Systems, Inc, Minneapolis, MN). The intra-assay and interassay coefficients of variation ranged from 3.8% to 4.4% and 4.1% to 6.1%, respectively (minimum detectable concentration, 0.025 ng/mL). High-sensitivity CRP was measured in serum by EIA (Immage hs-CRP EIA Kit; Beckman Coulter Inc, Brea, CA). Transthoracic echocardiography was performed, and biplane Simpson’s ejection fraction (%) was calculated before coronary angiography. Hypertension was defined as having at least 2 blood pressure measurements greater than 140/90 mm Hg or using antihypertensive drugs, whereas diabetes mellitus (DM) was defined as having at least 2 fasting blood sugar measurements greater than 126 mg/dL or using antidiabetic drugs. Smoking was categorized into current smokers and nonsmokers. Nonsmokers included ex-smokers who had quit smoking for at least 6 months before the study. Body mass index (BMI) values were calculated based on the height and weight of each patient. Medications used before the coronary angiography were noted. The study was approved by the local ethics committee.
SYNTAX and Gensini Scores
To grade the complexity of CAD, the SYNTAX score was used. Each coronary lesion with a stenosis diameter of 50% or greater in vessels of 1.5 mm or greater was scored. Parameters used in the SYNTAX scoring are shown in Table 1. The latest online updated version (2.11) was used in the calculation of the SYNTAX scores (www.syntaxscore.com).17 The SYNTAX score was classified as follows:

  1. low SYNTAX score (≤22),
  2. intermediate SYNTAX score (23–32)
  3. high SYNTAX score (≥33).

Table 1   http://images.journals.lww.com/jinvestigativemed/LargeThumb.00042871-201302000-00007.TT1.jpeg

The severity of CAD was determined by the Gensini score, which

  • measures the extent of coronary stenosis according to degree and location.18

In the Gensini scoring system,

  • larger segments are more heavily weighted ranging from 0.5 to 5.0
    • left main coronary artery × 5;
    • proximal segment of the left anterior descending coronary artery [LAD] × 2.5;
    • proximal segment of the circumflex artery × 2.5;
    • midsegment of the LAD × 1.5;
    • right coronary artery distal segment of the LAD,
    • posterolateral artery, and obtuse marginal artery × 1;
    • and others × 0.5.

The narrowing of the coronary artery lumen is rated

  1. 2 for 0% to 25% stenosis,
  2. 4 for 26% to 50%,
  3. 8 for 51% to 75%,
  4. 16 for 76% to 90%,
  5. 32 for 91% to 99%,
  6. 64 for 100%.

The Gensini index is the sum of the total weights for each segment. All angiographic variables of the SYNTAX and Gensini score were computed by

  • 2 experienced cardiologists who were blinded to the procedural data and clinical outcomes.

The final decision was reached by consensus when a conflict occurred.The number of diseased vessels with

  • greater than 50% luminal stenosis was scored from 1 to 3 (namely, 1-, 2-, or 3-vessel disease), and
  • a lesion greater than 50% in the left main coronary artery was regarded as a 2-vessel disease.

Statistical Analyses

Statistical analyses were conducted with SPSS 17 (SPSS Inc, Chicago, IL) software package program.
Continuous variables were expressed as mean ± SD or median ± interquartile range values, whereas categorical variables were presented as percentages.
The differences between normally distributed numeric variables were evaluated by Student t test or 1-way analysis of variance, whereas

  • non–normally distributed variables were analyzed by Mann-Whitney U test or Kruskal-Wallis variance analysis as appropriate.

χ2 Test was used for the comparison of categorical variables. Pearson test was used for correlation analysis.
To determine the independent predictors of “intermediate and high” SYNTAX scores and only “high” SYNTAX scores,

  • 2 different sets of univariate and multivariate analyses were performed
    • (in the first model SYNTAX cutoff was 22, whereas
    • in the second model SYNTAX cutoff was 33).

The standardized parameters that were found to have a significance (P < 0.10) in the univariate analysis were evaluated by stepwise logistic regression analysis.
Ninety-five percent confidence interval (CI) and odds ratio (OR) per SD increase were presented together. Interobserver and intraobserver variability for SYNTAX scores

  • was done by Bland-Altman analysis.

An exploratory evaluation of additional cut points was performed using the receiver operating characteristic (ROC) curve analysis.
All the P values were 2-sided, and a P < 0.05 was considered as statistically significant.
RESULTS
Baseline Characteristics
In total, 181 patients (50.2 ± 6.5 years, 52.5% were composed of males) were included in the study. Baseline clinical, angiographic, and laboratory characteristics of the patients
relative to SYNTAX score groups are shown in Table 2. Age, sex, HT, DM, BMI, and medication were not different between the groups. Baseline clinical and laboratory characteristics
of patients according to PTX-3 quartiles are shown in Table 3. The Bland-Altman analysis revealed that the degrees of intraobserver and interobserver variability for SYNTAX score
and Gensini score readings were 5% and 6% for SYNTAX and 8% and 9% for Gensini,
respectively.
Table 2   http://images.journals.lww.com/jinvestigativemed/Original.00042871-201302000-00007.TT2.jpeg
Table 3   http://images.journals.lww.com/jinvestigativemed/Original.00042871-201302000-00007.TT3.jpeg

The PTX-3 levels demonstrated an increase from the low SYNTAX group to the high SYNTAX group (r = 0.87, P < 0.001).
The low SYNTAX group had statistically significantly higher PTX-3 levels when compared with the control group (0.50 ± 0.01 vs 0.24 ± 0.01 ng/mL, P < 0.001); similarly,
the PTX-3 levels were higher in the high SYNTAX group than in both

  • the intermediate SYNTAX group (0.84 ± 0.08 vs 0.55 ± 0.01 ng/mL, P < 0.001) and
  • the low SYNTAX group (0.84 ± 0.08 vs 0.50 ± 0.01 ng/mL, P < 0.001).
  • there was no difference in levels of PTX-3 between the low and the intermediate SYNTAX group (0.50 ± 0.01 vs 0.55 ± 0.01 ng/mL, P = 0.09).

On the other hand, there was no difference in levels of hs-CRP between the control and the low SYNTAX group (0.81 ± 0.42 vs 0.86 ± 0.53 mg/dL, P = 0.96).
The intermediate SYNTAX group had statistically significantly higher hs-CRP levels

  • compared with the low SYNTAX group (1.3 ± 0.66 vs 0.86 ± 0.53 mg/dL, P = 0.002);
  • the hs-CRP levels were not different between the high SYNTAX group
    • and the intermediate SYNTAX group. (1.3 ± 0.66 vs 1.3 ± 0.43 mg/dL, P = 0.99).

Univariate correlation analysis revealed a positive correlation between serum PTX-3 levels and hs-CRP levels with

  • the SYNTAX and Gensini scores
    • for SYNTAX: r = 0.87 [P < 0.001] and r = 0.36 [P = 0.01];
    • for Gensini: r = 0.75 [P < 0.001] and r = 0.27 [P = 0.002],  (Fig. 1).

In addition to that, the Gensini and SYNTAX scores are found to be well correlated with each other (r = 0.80, P < 0.001).
When the SYNTAX score was taken as continuous variable, multivariate linear regression analysis revealed that

  • the SYNTAX score was correlated with PTX-3 and hs-CRP (for PTX-3: β = 0.84 [P < 0.001]; hs-CRP: β =0.08 [P = 0.032]).

Figure 1   http://images.journals.lww.com/jinvestigativemed/Original.00042871-201302000-00007.FF1.jpeg

For determining the predictors of intermediate and high SYNTAX scores and only-high SYNTAX scores,

  • 2 different sets of univariate and multivariate analyses were performed among the patients who underwent coronary angiography.

For predicting the intermediate and high SYNTAX scores, the SYNTAX score was dichotomized into

  • high (score ≥22) and
  • low (<22) groups,

whereas for predicting the only-high SYNTAX scores, the SYNTAX score was dichotomized into

  • 2 groups with a score of 33 or greater and a score of less than 33.

In the first multivariate analysis (where SYNTAX cutoff was 22), the parameters showing significance in the univariate analysis

  • age,
  • sex,
  • HT,
  • DM,
  • low-density lipoprotein cholesterol [LDL-C],
  • hs-CRP,
  • PTX-3

were evaluated by multivariate analysis to determine the

  • independent predictors of intermediate and high SYNTAX scores.

In the univariate analysis, higher values of

  • age (OR, 1.5 [95% CI, 1.1–2.0]; P = 0.01),
  • LDL-C (OR, 1.3 [95% CI, 0.98–1.8]; P = 0.068),
  • hs-CRP (OR, 2.6 [95% CI, 1.8–3.8]; P < 0.001), and
  • PTX-3 (OR, 13.6 [95% CI, 6.4–28.9]; P < 0.001)
    • were associated with higher SYNTAX scores,
  • HT (OR, 0.44 [95% CI, 0.24–0.80]; P = 0.008) and
  • DM (OR, 0.48 [95% CI, 0.25–0.91]; P = 0.02)
    • were associated with lower SYNTAX scores.

In the multivariate analysis – age, DM, LDL-C, hs-CRP, and PTX-3 – were found to be

  • independent predictors of “intermediate to high” SYNTAX score (Table 4).

Increased

  • age (OR, 2.5 [95% CI, 1.3–4.8]; P = 0.007),
  • LDL-C (OR, 2.8 [95% CI, 1.5–5.2]; P = 0.001),
  • hs-CRP (OR, 3.3 [95% CI, 1.8–6.1]; P < 0.001), and
  • PTX-3 (OR, 35.4 [95% CI, 10.1–123.6]; P < 0.001)
    • were associated with increased SYNTAX scores,

whereas DM (OR, 0.08 [95% CI, 0.02–0.33]; P < 0.001) was associated with lower SYNTAX score (Table 4).

In the second univariate and multivariate analyses (where SYNTAX cutoff was 33),

  • the parameters that showed significance in the univariate analysis were age, LDL-C, glucose, hs-CRP, and PTX-3.
  • In the univariate analysis, increased
    • age (OR, 1.5 [95% CI, 1.0–2.3]; P = 0.05),
    • LDL-C (OR, 1.5 [95% CI, 0.97–2.2]; P = 0.07),
    • hs-CRP (OR, 1.4 [95% CI, 0.97–2.1]; P = 0.072), and
    • PTX-3 (OR, 18.5 [95% CI, 6.6–51.8]; P < 0.001)
      • were found to be associated with increased SYNTAX scores.

When these parameters were evaluated with multivariate analysis, only PTX-3 (OR, 18.4 [95% CI, 6.2–54.2]; P < 0.001)

    • was found to be an independent predictor for high SYNTAX score (Table 4).

Table 4   http://images.journals.lww.com/jinvestigativemed/Original.00042871-201302000-00007.TT4.jpeg

The ROC curve analysis further revealed that the PTX-3 level was a strong indicator of high SYNTAX score with

  • an area under the curve (AUC) of 0.91 (95% CI, 0.86–0.96) (Fig. 2).

The optimal cutoff of PTX-3 for the high SYNTAX score was 0.75 ng/mL.
Sensitivity, specificity, positive predictive value, and negative predictive value to identify high SYNTAX score for the PTX-3 level

  • were 90%, 84%, 97%, and 60%, respectively.
  • the ROC curve analysis of PTX-3 for intermediate-high SYNTAX score revealed that the AUC value was 0.82 (95% CI, 0.75–0.89).

The optimal threshold of PTX-3 level that

  • maximized the combined specificity and sensitivity to predict
    • intermediate to high SYNTAX score was 0.73 ng/mL.

For the cutoff value of 0.73 ng/mL, sensitivity, specificity, positive predictive value, and negative predictive value

  • to identify intermediate-high SYNTAX score were 56%, 98%, 97%, and 56%, respectively.

Figure 2   http://images.journals.lww.com/jinvestigativemed/Original.00042871-201302000-00007.FF2.jpeg

In the ROC analysis of hs-CRP for high SYNTAX scores, the AUC value was found to be 0.68 (95% CI, 0.59–0.77; P < 0.001).
The optimal threshold of hs-CRP that maximized the combined specificity and sensitivity to predict for high SYNTAX scores was 0.89 mg/dL.
Similarly, the ROC analysis of hs-CRP for the intermediate-high SYNTAX scores revealed an AUC of 0.74 (95% CI, 0.65–0.83; P = 0.001).
The cutoff value of hs-CRP to predict the intermediate-high SYNTAX scores with a maximized sensitivity and specificity was 0.66 mg/dL.
DISCUSSION
In this particular study, we investigated the relationship between the serum PTX-3 level and the severity of CAD

  • assessed by SYNTAX and Gensini scores in patients with SAP.

The PTX-3, was significantly higher than control group in the patients with CAD, and the serum PTX-3 levels

  • were associated with the SYNTAX and Gensini scores.

When compared with the hs-CRP, the PTX-3 was found to be more tightly associated with the complexity and severity of CAD in the patients with SAP.
Pentraxin 3, an acute-phase reactant that is functionally and structurally similar to CRP,1 is produced both by different kinds of cells such as

  • macrophages, dendritic cells, neutrophils, fibroblasts, and vascular endothelial cells.2
  • Pentraxin 3 is released following the inflammatory stimuli19; therefore, it may reflect the local inflammatory status in tissues.20

Serum PTX-3 levels were shown to be elevated in patients with

  • vasculitis,6 acute myocardial infarction,7,8 and systemic inflammation or sepsis,9 psoriasis, unstable angina pectoris, and heart failure.10–13

Higher PTX3 levels were reported to be associated with worse cardiovascular outcomes

  1. after acute coronary syndromes,8,21
  2. in the elderly people without known cardiovascular disease22 and
  3. associated with overall mortality in patients with stable coronary disease,
  4. independent of systemic inflammation.14

There are 2 reports investigating the association of PTX-3 level and the atherosclerotic burden.15,16 In one of these reports,

  • Knoflach et al.15 took B-mode ultrasonography as the atherosclerosis index.

They did not provide any information about coronary anatomy, and in the other report, Soeki et al.16 evaluated 40 patients who

  • underwent coronary angiography and measured their Gensini scores.

However, in none of the studies were the SYNTAX score and Gensini score used together to assess the degree of coronary atherosclerotic burden.
To our knowledge, this is the first report that showed the association of PTX-3 levels with the complexity and severity of CAD assessed by

  • SYNTAX and Gensini scores in patients with stable coronary disease.

Chronic low-grade inflammation has been thought to play a major role in the pathogenesis of atherosclerosis.23,24 Previous studies have reported that

  • levels of inflammatory markers such as hs-CRP, interleukin 6, and so on were increased in atherosclerosis.25

In the present study, both the SYNTAX and the Gensini scores were found to be correlated with serum PTX-3 and hs-CRP levels,

  • which in turn might reflect the degree of inflammation.

The SYNTAX score is an important tool in the classification of complex CAD26 and can give predictive information about short- and long-term outcomes

  • in patients with stable CAD who undergo percutaneous coronary intervention.27–30

Although the SYNTAX score is currently used for assessing the angiographic complexity of CAD rather than the severity of coronary atherosclerotic burden,

  • because more complex lesions tend to have more atherosclerotic burden,
  • the SYNTAX scores may also reflect the severity of coronary atherosclerotic burden.

The Gensini score, a well-known and widely used scoring system to evaluate the severity of CAD,18 was measured and

  • found to be well correlated with the SYNTAX score,
    • which supports the idea that angiographically more complex lesions tend to have more atherosclerotic burden.

When compared with the hs-CRP,

  • the PTX-3 seems to be more tightly associated with coronary disease burden (r = 0.36 vs r = 0.87).

We found out that the serum PTX-3 levels were higher than those in the control group, even in the low SYNTAX group.
On the other side, the serum hs-CRP levels were not different in the control and the low SYNTAX groups.
It was reported that the leukocytes mainly found in the coronary artery lumen are the neutrophils.31
It is also known that PTX-3 is stored in specific granules of neutrophils and released in response to inflammatory signals.32
The reason why serum PTX-3 levels seem more tightly associated with the coronary disease burden

  • when compared with serum hs-CRP levels may be the association of the
  • on-site presence of neutrophils and local inflammatory signal–triggered release of  PTX-3.

On the other hand, some human studies revealed that PTX-3 was produced more in areas of atherosclerosis and may contribute to its pathogenesis.31
Some other studies suggested that PTX-3 may be part of a protective mechanism in

  • vascular repair via inhibiting fibroblast growth factor 2 or some other growth factors responsible for smooth muscle proliferation.33,34

But still, the exact role of PTX-3 in the pathophysiology of atherosclerosis seems to be obscure for the time being. It is well established that atherosclerosis
has an inflammatory background in most of the cases. In addition to that, high blood CRP level is known as an indicator of future cardiovascular disease risk
even in healthy individuals.35 According to the results of univariate and multivariate analyses, for intermediate and high SYNTAX scores,

  1. age, DM, LDL-C, hs-CRP, and PTX-3 were found to be independent predictors, whereas for the presence of
  2. high SYNTAX score, only PTX-3 was found to be an independent predictor.

Because of the tighter association with atherosclerotic burden and the on-site vascular presence,

    • PTX-3 may be a promising candidate marker for vascular inflammation and future cardiovascular events.

LIMITATIONS
The major limitation of the current study is the number of patients included. It would be better to include more patients to increase the statistical power.

Besides, the SYNTAX and Gensini scores give us an idea about the complexity and severity of coronary atherosclerosis; however,
with coronary angiography alone, it is not possible to understand the extent of coronary plaque. In addition to that, the coronary anatomy of the
control group was not known, which was another limitation. Our selected population was free of other confounders of systemic inflammation, and
we did not have data about inflammatory markers other than hs-CRP, such as interleukin 6, tumor necrosis factor α, and so on, which may be accepted
as a limitation. Another limitation of the current study is that because there was no long-term follow-up of the patients, it did not provide any prognostic
data in terms of future cardiovascular events.
CONCLUSIONS
Pentraxin 3, a novel inflammatory marker, is associated with the complexity and severity of the CAD assessed by the SYNTAX and the Gensini scores in patients with SAP and seems to be more tightly associated with coronary atherosclerotic burden than hs-CRP.

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12. Suzuki S, Takeishi Y, Niizeki T, et al.. Pentraxin 3, a new marker for vascular inflammation, predicts adverse clinical outcomes in patients with heart failure. Am Heart J. 2008; 155: 75–81.
13. Matsubara J, Sugiyama S, Nozaki T, et al.. Pentraxin 3 is a new inflammatory marker correlated with left ventricular diastolic dysfunction and heart failure with normal ejection fraction. J Am Coll Cardiol. 2011; 57: 861–869.
14. Dubin R, Li Y, Ix JH, et al.. Associations of pentraxin-3 with cardiovascular events, incident heart failure, and mortality among persons with coronary heart disease: data from the Heart and Soul Study. Am Heart J. 2012; 163: 274–279.
16. Soeki T, Niki T, Kusunose K, et al.. Elevated concentrations of pentraxin 3 are associated with coronary plaque vulnerability. J Cardiol. 2011; 58: 151–157.
17. SYNTAX working group. SYNTAX score calculator. Available at http://www.syntaxscore.com. Accessed May 20, 2012.
18. Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol. 1983; 51: 606.
20. Mantovani A, Garlanda C, Bottazzi B, et al.. The long pentraxin PTX3 in vascular pathology. Vascul Pharmacol. 2006; 45: 326–330.
21. Matsui S, Ishii J, Kitagawa F, et al.. Pentraxin 3 in unstable angina and non-ST-segment elevation myocardial infarction. Atherosclerosis. 2010; 210: 220–225.
22. Jenny NS, Arnold AM, Kuller LH, et al.. Associations of pentraxin 3 with cardiovascular disease and all-cause death: the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol. 2009; 29: 594–599.
26. Serruys PW, Morice MC, Kappetein AP, et al.. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009; 360: 961–972.
27. van Gaal WJ, Ponnuthurai FA, Selvanayagam J, et al.. The SYNTAX score predicts peri-procedural myocardial necrosis during percutaneous coronary intervention. Int J Cardiol. 2009; 135: 60–65.
28. Lemesle G, Bonello L, de Labriolle A, et al.. Prognostic value of the SYNTAX score in patients undergoing coronary artery bypass grafting for three-vessel coronary artery disease. Catheter Cardiovasc Interv. 2009; 73: 612–617.
29. Capodanno D, Di Salvo ME, Cincotta G, et al.. Usefulness of the SYNTAX score for predicting clinical outcome after percutaneous coronary intervention of unprotected left main coronary artery disease. Circ Cardiovasc Interv. 2009; 2: 302–308.
30. Kim YH, Park DW, Kim WJ, et al.. Validation of SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score for prediction of outcomes after unprotected left main coronary revascularization. JACC Cardiovasc Interv. 2010; 3: 612–623.
32. Jaillon S, Peri G, Delneste Y, et al.. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J Exp Med. 2007; 204: 793–804.
33. Inforzato A, Baldock C, Jowitt TA, et al.. The angiogenic inhibitor long pentraxin PTX3 forms an asymmetric octamer with two binding sites for FGF2. J Biol Chem. 2010; 285: 17681–17692.
34. Camozzi M, Zacchigna S, Rusnati M, et al.. Pentraxin 3 inhibits fibroblast growth factor 2–dependent activation of smooth muscle cells in vitro and neointima formation in vivo. Arterioscler Thromb Vasc Biol. 2005; 25: 1837–1842.
35. Koenig W, Sund M, Frohlich M, et al.. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation. 1999; 99: 237–242.
Keywords:  pentraxin 3; coronary artery disease; SYNTAX score; hs-CRP; inflammation

This is not the only recent finding that adds to the ability to evaluate these patients.  An as yet unpublished paper, expected to be published soon reports on

QRS fragmentation as a Prognostic test in Acute Coronary Syndrome,  and this reviewer expects the work to have a high impact.  The authors state that
QRS complex fragmentation is a promising bed-side test for assessment of prognosis in those patients.  Presence of fragmented QRS in surface ECG during ACS

  • represents myocardial scar or fibrosis and reflect severity of coronary lesions and a correlation between fQRS and depression of Lv function is established.

There are still other indicators that need to be considered, such as the mean arterial blood pressure.

There has been review and revisions of the guidelines for treatment of UA/NSTEMI within the last year, with differences being resolved among the Europeans and US.

Guidelines Updated for Unstable Angina/Non-ST Elevation Myocardial Infarction
According to the current study by Jneid and colleagues, new evidence is available on the management of unstable angina. This report replaces the 2007 American College of Cardiology Foundation/American Heart Association (ACC/AHA) Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction (UA/NSTEMI) that were updated by the 2011 guidelines.

This guideline was reviewed by

  • 2 official reviewers each nominated by the ACCF and the AHA, as well as
  • 1 or 2 reviewers each from the American College of Emergency Physicians; the Society for Cardiovascular Angiography and Interventions; and the Society of Thoracic Surgeons; and
  • 29 individual content reviewers, including members of the ACCF Interventional Scientific Council.

The recommendations in this focused update are considered current

  • until they are superseded in another focused update or the full-text guideline is revised, and are official policy of both the ACCF and the AHA.

STUDY SYNOPSIS AND PERSPECTIVE
American cardiology societies have caught up with the European Society of Cardiology by

  • issuing their second update to the UA/NSTEMI guidelines in 18 months,
  • with the 2012 focused update replacing the 2011 guidelines [1].

The new recommendations include ticagrelor (Brilinta) as one of the options for antiplatelet therapy alongside prasugrel (Effient) and clopidogrel, bringing them in line with European.
The European guidance, however, gave precedence to the new antiplatelets over clopidogrel, whereas the American update “places ticagrelor on an equal footing with the other two antiplatelets available
this is the main reason for the update,” lead author Dr Hani Jneid (Baylor College of Medicine, Houston, TX), told heartwire . “Doctors now have a choice for second-line therapy after aspirin, depending on

  • the patient’s clinical scenario,
  • physician preference, and cost,”
    • now that clopidogrel is available generically.

The US decision to recommend

  • first prasugrel–in its 2011 update to the UA/NSTEMI guidelines–and
  • now ticagrelor as equivalent antiplatelet therapy choices to clopidogrel after aspirin
    • puts it somewhat at odds with the Europeans,
    • who reserve clopidogrel use for those who cannot take the newer agents.

The reason for the Americans differing stance is that because while they are faster acting and more potent–

  • the cost-effectiveness of the new agents is not known.
  • it isn’t clear how the efficacy observed in pivotal clinical trials of these agents is going to translate into real-world benefit,
  • and issues such as bleeding with prasugrel and compliance with a twice-daily drug such as ticagrelor remain concerns.

Bulk of 2012 Update on How to Use Ticagrelor
The 2012 ACCF/AHA focused update for the management of UA/NSTEMI stresses that

  • all patients at medium/high risk should receive dual antiplatelet therapy on admission,
  • with aspirin being first-line, indefinite therapy.

The bulk of the update centers on how to use ticagrelor which–

  • like prasugrel or clopidogrel–
  • can be added to aspirin for up to 12 months (or longer, at the discretion of the treating clinician).

Jneid notes it’s important to remember that prasugrel can only be used in the cath lab

  • in patients undergoing percutaneous coronary intervention (PCI),
  • whereas ticagrelor, like clopidogrel, can be used in medically managed or PCI patients.

And he emphasizes that, in line with the FDA’s black-box warning on ticagrelor,

The 81-mg aspirin dose is also considered a reasonable option in preference to a higher maintenance dose of 325 mg in

  • any acute coronary syndrome (ACS) patient following PCI, he adds, as
  • this strategy is believed to result in equal efficacy and lower bleeding risk.

With regard to how long antiplatelet therapy should be stopped before planned cardiac surgery, the recommendation is

  • five days for ticagrelor–the same as that advised for clopidogrel.
  • and seven days prior to surgery for prasugrel.

Jneid also highlights other important recommendations from the 2011 focused update carried over to 2012:

It is “reasonable” to proceed with cardiac catheterization and revascularization within

  • 12–24 hours of admission in initially stable, very high-risk patients with ACS.

An invasive strategy is “reasonable” in patients with

  • mild and moderate chronic kidney disease.

In those with diabetes hospitalized with ACS, insulin use should target glucose levels <180 mg/dL,

  • a less-intensive reduction than previously recommended.

Platelet function or genotype testing for clopidogrel resistance are both considered “reasonable”

  • if clinicians think the results will alter management,
  • but Jneid acknowledged that “there is not much evidence to support these assays” .

Committee Encourages Participation in Registries
Jneid observes that unstable angina and NSTEMI are “very common” conditions that carry a high risk of death and recurrent heart attacks,

  • which is why “the AHA and ACCF constantly update their guidelines so that physicians can provide patients with
  • the most appropriate, aggressive therapy with the goal of improving health and survival.”

To this end, he notes that the writing panel encourages

  • clinicians and hospitals to participate in quality-of-care registries designed
  • to track and measure outcomes, complications, and
  • adherence to evidence-based medicines.

Conflicts of interest for the writing committee are listed in the paper.

References

Jneid H, Anderson JL, Wright SR, et al. 2012 ACCF/AHA focused update on the guideline for the management of patients with unstable angina/non-ST elevation myocardial infarction (Updating the 2007 guideline and replacing the 2011 focused update): A report of the ACCF/AHA.
Circulation 2012;      Available at: http://circ.ahajournals.org/  http://dx.doi.org/10.1161/CIR0b013e3182566fleo
source   http://www.medscape.org

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Curator & Reporter: Aviva Lev-Ari, PhD, RN

C-Reactive Protein, Fibrinogen, and Cardiovascular Risk

N Engl J Med 2013; 368:84-86 January 3, 2013DOI: 10.1056/NEJMc1213688

To the Editor:

Kaptoge and colleagues (Oct. 4 issue)1 suggest that C-reactive protein (CRP) and fibrinogen, two biomarkers of inflammation, have a significant though limited incremental prognostic value when added to conventional risk factors. However, the implied ordering of risk factors on the basis of the chronology of their identification as risk factors should be challenged and replaced by an ordering that is based on their effect on prognostic accuracy. The hazard ratios for cardiovascular events (Table 1 of the article) for CRP or fibrinogen levels are in the range of those for established lipid risk factors and even blood pressure. Moreover, data shown in the Supplementary Appendix only (Table S4 and Fig. S4 in the Supplementary Appendix, available with the full text of the article at NEJM.org) reveal that adding the CRP or fibrinogen level to or omitting it from various risk-factor combinations produces differences in the C-index similar to those obtained when diabetes, the total cholesterol level, or the high-density lipoprotein (HDL) cholesterol level is added to or omitted from risk-factor combinations. These data call for an unbiased view of risk factors for cardiovascular disease that place the significance of biomarkers of inflammation such as CRP concentrations at the same level as conventional risk factors, rather than as a final low-impact increment.

Thomas M. Stulnig, M.D.
Medical University of Vienna, Vienna, Austria
thomas.stulnig@meduniwien.ac.at

No potential conflict of interest relevant to this letter was reported.

1 References

To the Editor:

In the Emerging Risk Factors Collaboration study involving 246,669 participants, Kaptoge et al. find that, on average, the CRP level was associated with a significant improvement in the prediction of cardiovascular disease, beyond that observed with classical risk factors. However, it was not predictive among women and in the analysis of the risk of stroke, indicating that the CRP level cannot be used as a one-size-fits-all marker of cardiovascular risk.

The prognostic value of the CRP level was first reported in patients with severe unstable angina1and subsequently also in healthy populations. Genetic studies did not support a pathogenetic role for CRP level in cardiovascular disease.2 A CRP cutoff point of at least 2 mg per liter has been proposed for the initiation of statin therapy,3 but in three ethnic groups, 41% of patients with ST-segment elevation myocardial infarction had CRP levels below this threshold.4 Thus, they would not have been eligible for such a preventive strategy.

The limited specificity and sensitivity of CRP measurements for predicting global cardiovascular disease risk suggest the need for appropriate studies of benefit in individual patients before the adoption of one-size-fits-all paradigms, which can be statistically relevant for study populations, with considerable health care costs, but not for the treatment of individual patients.

Enrico Ammirati, M.D.
San Raffaele Scientific Institute, Milan, Italy

Attilio Maseri, M.D.
Heart Care Foundation, Florence, Italy
amaseri@heartcarefound.org

No potential conflict of interest relevant to this letter was reported.

4 References

To the Editor:

Kaptoge et al. report that the measurement of CRP or serum fibrinogen levels would identify 13,199 patients who could potentially benefit by a reduction of 30 events (fatal or nonfatal) over the course of 10 years, owing simply to a reclassification of risk and application of statin therapy. Were the test to have no cost, statin therapy to have neither side effects nor no excess cost of follow-up, and drug costs to be limited to $1,000 over the period of 10 years (all unreasonably low assumptions), the cost per event avoided would be greater than $15 million, or more than $500,000 per event. Not reporting the expected effect of such an approach on costs abrogates our responsibility to the community. I propose that an additional step be added that requires that we (as authors and journals) analyze the financial implications of our scientific observations.

Larry A. Weinrauch, M.D.
Harvard Medical School, Boston, MA
lweinrauch@hms.harvard.edu

No potential conflict of interest relevant to this letter was reported.

Author/Editor Response

In the Emerging Risk Factors Collaboration study, a meta-analysis of individual participant data from almost 250,000 people in 52 prospective studies, we found that information on biomarkers of inflammation such as CRP or fibrinogen level improved the prediction of first-onset cardiovascular disease outcomes when added to conventional risk factors. We conclude that the assessment of CRP or fibrinogen level in persons classified as being at intermediate risk (i.e., a predicted 10-year risk of cardiovascular disease of 10% to <20% on the basis of conventional risk factors alone) could help prevent one additional cardiovascular disease event over a period of 10 years for every 400 to 500 people so screened, assuming initiation of statin therapy according to the Adult Treatment Panel III guidelines.

We agree with Stulnig that the sequence in which risk factors are included in prediction models can influence their comparative effect. Our report focuses on the incremental value of biomarkers of inflammation, because current guidelines debate the value of adding them to conventional risk factors. However, as Stulnig notes, we also provide information showing that the separate predictive values for CRP, fibrinogen, total cholesterol, and HDL cholesterol levels were similar in analyses that did not depend on the sequence in which they were used. The order in which risk factors should be considered may depend on various factors (e.g., convenience, cost, and promotion of lifestyle changes to reduce the risk of cardiovascular disease).

Ammirati and Maseri suggest that the scoring for cardiovascular disease risk needs to be refined. Partly for this reason, we present findings for a range of clinically relevant subgroups, suggesting improvement in the prediction of cardiovascular disease with inflammation biomarkers that is apparently lower in women than in men. However, because these subgroup analyses were exploratory in nature, we believe that they require cautious interpretation until they can be confirmed in independent studies.

Weinrauch makes a rough estimate of the financial implications of our findings, assuming that only drug costs of $1,000 per person over a period of 10 years apply. Unfortunately, his calculations are overestimates by a factor of 20, since, according to the results of our study, drug costs would be limited to the 690 people treated after the additional assessment of CRP level, rather than all the 15,025 people initially classified as being at intermediate risk. Using Weinrauch’s figures, the cost would be $23,000 per cardiovascular disease event prevented over the course of 10 years, not $500,000. More generally, since simplistic financial calculations may be misleading, we encourage detailed cost-effectiveness evaluation,1 as stated in our report.

Stephen Kaptoge, Ph.D.
Simon G. Thompson, D.Sc.
John Danesh, M.D.
University of Cambridge, Cambridge, United Kingdom
erfc@phpc.cam.ac.uk

for the Emerging Risk Factors Collaboration

Since publication of their article, the authors report no further potential conflict of interest.

SOURCE:

http://www.nejm.org/doi/full/10.1056/NEJMc1213688?goback=%2Egde_72923_member_200638106

Other articles related to this subject matter appeared on this Open Access Online Scientific Journal:

PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity

https://pharmaceuticalintelligence.com/2013/01/10/pci-outcomes-increased-ischemic-risk-associated-with-elevated-plasma-fibrinogen-not-platelet-reactivity/

Assessing Cardiovascular Disease with Biomarkers

https://pharmaceuticalintelligence.com/2012/12/25/assessing-cardiovascular-disease-with-biomarkers/

What is the role of plasma viscosity in hemostasis and vascular disease risk?

https://pharmaceuticalintelligence.com/2012/11/28/what-is-the-role-of-plasma-viscosity-in-hemostasis-and-vascular-disease-risk/

Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.

https://pharmaceuticalintelligence.com/2012/10/30/cardiovascular-risk-inflammatory-marker-risk-assessment-for-coronary-heart-disease-and-ischemic-stroke-atherosclerosis/

A second look at the transthyretin nutrition inflammatory conundrum

https://pharmaceuticalintelligence.com/2012/12/03/a-second-look-at-the-transthyretin-nutrition-inflammatory-conundrum/

Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

https://pharmaceuticalintelligence.com/2012/11/28/special-considerations-in-blood-lipoproteins-viscosity-assessment-and-treatment/

Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles

https://pharmaceuticalintelligence.com/2012/12/29/coronary-artery-disease-in-symptomatic-patients-referred-for-coronary-angiography-predicted-by-serum-protein-profiles/

Read Full Post »


Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis

Reporter: Aviva Lev-Ari, PhD, RN

 

Updated on 10/3/2018

Treatment concentration of high-sensitivity C-reactive protein

Published:November 13, 2017DOI:https://doi.org/10.1016/S0140-6736(17)32865-9

Interleukin 1β has multiple potential mechanisms that contribute to the pathogenesis of atherothrombotic cardiovascular disease.

Induction of interleukin 6 leads to the release of acute phase reactants including hsCRP. Thus, hsCRP serves as a surrogate marker of the overall inflammatory milieu,

often in situations where patients have multiple co-morbidities,

with a cumulative dose-response indicating a higher risk.

References

  • Ridker PM
  • Everett BM
  • Thuren T
  • et al.
Antiinflammatory therapy with canakinumab for atherosclerotic disease.

N Engl J Med. 2017; 3771119-1131

  • Libby P
Interleukin-1 beta as a target for atherosclerosis therapy: biological basis of CANTOS and beyond.

J Am Coll Cardiol. 2017; 702278-2289

  • Pokharel Y
  • Sharma PP
  • Qintar M
  • et al.
High-sensitivity C-reactive protein levels and health status outcomes after myocardial infarction.

Atherosclerosis. 2017; 26616-23

  • Wang A
  • Liu J
  • Li C
  • et al.
Cumulative exposure to high-sensitivity C-reactive protein predicts the risk of cardiovascular disease.

J Am Heart Assoc. 2017; 6e005610

    • Ridker PM
    • MacFadyen JG
    • Everett BM
    • et al.

on behalf of the CANTOS Trial Group

Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial.

Lancet. 2017; (published online Nov 13.)

SOURCE

 

 

 

 

Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic StrokeAtherosclerosis.

 

Watch VIDEO

webinar

Lp-PLA2 Overview Webinar

Source: http://www.plactest.com/healthcare/webinar

Watch VIDEO

 american-heart-association-2007-lppla2-highlights

American Heart Association 2007 Lp-PLA2 Presentation

Source: http://www.plactest.com/healthcare/american-heart-association-2007-lppla2-highlights

diaDexus’s PLAC, the test measuting Lp-PLA2 as a novel and valuable cardiovascular risk inflammatory marker a vascular-specific inflammatory marker implicated in the formation of rupture-prone plaque, and is the only blood test cleared by the FDA to assess risk for coronary heart disease and ischemic stroke associated with atherosclerosis. (2003 and in 2005 received additional clearance as an aid in the assessment of risk for ischemic stroke associated with atherosclerosis.)

 

In 2007 the PLAC Test was granted a Category I CPT Code (83698) by the American Medical Association and is reimbursed by the Centers for Medicare and Medicaid Services (CMS) with a National Limitation Amount (NLA) of $47.77 in the 2011 CMS Clinical Laboratory Fee Schedule.

In July 2010, diaDexus completed a reverse merger with VaxGen. diaDexus currently trades on the OTC Bulletin Board (DDXS.OB).

 

PLAC Test is an alternative to C- Reactive Protein Test

 

The PLAC® Test is a simple blood test to detect Lp-PLA2 in the bloodstream. It is used to help predict risk for coronary heart disease and ischemic stroke associated with atherosclerosis.

 

  • The PLAC Test measures Lp-PLA2
    (lipoprotein-associated phospholipase A2), a vascular-specific inflammatory enzyme implicated in the formation of rupture-prone plaque. It is plaque rupture and thrombosis, not stenosis, that causes the majority of cardiac events.
  • A substantial body of evidence, including over 100 studies and abstracts in peer-reviewed journals and conferences, support Lp-PLA2 as a cardiovascular risk marker that provides new information, over and above traditional risk factors.
  • Consistent with ATP III and European guidelines, the PLAC Test should be used as an adjunct to traditional risk factor assessment to identify which moderate or high risk patients, as initially assessed by traditional risk factors, may actually be at higher risk.
  • An elevated PLAC Test may indicate a need for more aggressive patient management.
    • 50% of cardiovascular events strike in patients with unremarkable lipid levels, highlighting the prevalence of hidden cardiovascular risk.
    • LDL-C and total cholesterol have proven not to be reliable predictors of stroke; the PLAC Test addresses this unmet clinical need.
  • Lipid lowering therapies, including statins, are proven to reduce cardiovascular events regardless of baseline LDL-C levels.

 

Basic Science of Lp-PLA2

The PLAC® Test measures Lp-PLA2 (lipoprotein-associated phospholipase A2) a vascular-specific inflammatory enzyme implicated in the formation of rupture-prone plaque. It is plaque rupture and thrombosis that cause the majority of cardiac events, not stenosis.

 

 

 

 

Lp-PLA2 is a calcium-independent serine lipase that is associated with both low-density lipoprotein (LDL) and, to a lesser extent, high-density lipoprotein (HDL) in human plasma and serum and is distinct from other phospholipases such as cPLA2 and sPLA2. Lp-PLA2 is produced by macrophages and other inflammatory cells and is expressed in greater concentrations in advanced atherosclerotic lesions than early-stage lesions.

 

Lp-PLA2 has demonstrated modest intra- and inter-individual variation, commensurate with other cardiovascular lipid markers and substantially less than C-reactive protein (CRP). In addition, Lp-PLA2 is not elevated in systemic inflammatory conditions, and may be a more specific marker of vascular inflammation. The relatively small biological variation of Lp-PLA2 and its specificity are of value in the detection and monitoring of cardiovascular risk.

SOURCE:

http://www.plactest.com/healthcare/basic-science.html

 

 

Clinical Utility of the PLAC Test

 

The PLAC® Test Measures Lp-PLA2, a Unique Marker  
The PLAC Test for Lp-PLA2 is the only blood test cleared by the FDA to aid in assessing risk for both coronary heart disease and ischemic stroke associated with atherosclerosis. The PLAC Test measures lipoprotein-associated phospholipase A2 (Lp-PLA2), a vascular-specific biomarker implicated in the formation of rupture-prone plaque. The majority of all heart attacks and strokes are caused by plaque rupture and thrombosis (clots) – not stenosis (narrowing of arteries).

Lp-PLA2 is a unique marker for vascular-specific inflammation and is produced by macrophages in inflamed plaque. Lp-PLA2 provides additive risk information when combined with other markers such as hs-CRP to help you personalize your treatment options, beyond the limitations of the traditional cardiovascular (CV) risk factors.

The PLAC Test Helps Identify Hidden Risk
Lp-PLA2 is an independent risk marker for stroke. At every level of blood pressure, an Lp-PLA2 value above the median almost doubles the risk for stroke.  Current stroke guidelines include consideration of Lp-PLA2 measurement in asymptomatic patients to identify those who may be at increased risk of stroke.

The PLAC Test Helps Improve Patient Management 
Periodic measurement of the amount of Lp-PLA2 in the blood for patients with 2 or more CVD risk factors can aid clinical decisions for at-risk patients, allowing you to assess or reassess the effect of lipid lowering therapies on vascular inflammation, intensify therapeutic lifestyle changes, and reinforces doctors’ recommendations for patient management.

 

 

 

 

Essential Information to Guide Treatment

In accordance with ATP III Guidelines, patients with 2 or more CV risk factors may be candidates for advanced lipid testing.

Measure the amount of Lp-PLA2 in your patient’s blood stream with the PLAC Test to determine whether they may be at increased risk for heart attack or stroke.

If the PLAC Test results are 200 ng/mL or greater, cardiovascular disease may be present. Review your patient’s advanced lipid panel results to determine where more aggressive patient management may be needed.

 

* additional reduction of Lp-PLA2 seen when added to statin therapy.

Based on:

Shalwitz R, et al. ATVB Annual Mtg. 2007.

Kuvin J, et al. Am J Cardiol. 2006.

Albert M, et al. Atherosclerosis 2005.

Schaefer EJ, et al. Am J Cardiol. 2005.

Saougos VG, et al. ATVB 2007.

Muhlestein JB, et al. JACC 2006.

      Early detection and more aggressive treatment can help prevent cardiovascular events.


 

SOURCE:

http://www.plactest.com/Default.aspx?PageID=4620488&A=PrinterView

 

 

REFERENCES

 

Pathophysiology and Genetics Studies

 

A Twin Study of Heritability of Plasma Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Mass and ActivityLenzini L, Antezza K, Caroccia B, Wolfert RL, Szczech R, Cesari M, Narkiewicz K, Williams CJ, Rossi GP. A Twin Study of Heritability of Plasma Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Mass and Activity. Atherosclerosis. 2009; 205(1): 181-5.

Enhanced Expression of Lp-PLA2 and Lysophosphatidylcholine in Symptomatic Carotid Atherosclerotic PlaqueMannheim D, Herrmann J, Versari D, Gössl M, Meyer FB, McConnell JP, Lerman LO, Lerman A. Enhanced Expression of Lp-PLA2 and Lysophosphatidylcholine in Symptomatic Carotid Atherosclerotic Plaque. Stroke. 2008; 39: 1448-55.

Expression of Lipoprotein-Associated Phospholipase A2 in Carotid Artery Plaques Predicts Long-term Cardiac OutcHerrmann J, Mannheim D, Wohlert C, Versari D, Meyer FB, McConnell JP, Gössl M, Lerman LO, Lerman A. Expression of Lipoprotein-Associated Phospholipase A2 in Carotid Artery Plaques Predicts Long-term Cardiac Outcome. Eur. Heart J. 2009 Dec; 30(23): 2930-8.

Lipoprotein-Associated Phospholipase A2 is an Independent Marker for Coronary Endothelial Dysfunction in HumansYang EH, McConnell JP, Lennon RJ, Barsness GW, Pumper G, Hartman SJ, Rihal CS, Lerman LO, Lerman A. Lipoprotein-Associated Phospholipase A2 is an Independent Marker for Coronary Endothelial Dysfunction in Humans. Arterioscler Thromb Vasc Biol. 2006; 26(1): 106-11.

Lipoprotein-Associated Phospholipase A2 Protein Expression in the Natural Progression of Human Coronary AtherosclerosisKolodgie FD, Burke AP, Skorija KS, Ladich E, Kutys R, Makuria AT, Virmani R. Lipoprotein-Associated Phospholipase A2 Protein Expression in the Natural Progression of Human Coronary Atherosclerosis. Arterioscler Thromb Vasc Biol. 2006; 26: 2523-9.

 

Therapeutic Modulation Studies

 

Cardiovascular Events With Increased Lipoprotein-Associated Phospholipase A2 and Low High-Density Lipoprotein-Cholesterol. The Veterans Affairs HDL Intervention Trial.Robins SJ, Collins D, JJ, Bloomfield HE, Asztalos BF. Cardiovascular Events With Increased Lipoprotein-Associated Phospholipase A2 and Low High-Density Lipoprotein-Cholesterol. The Veterans Affairs HDL Intervention Trial. Arterioscler Thromb Vasc Biol. 2008; 28(6): 1172-8.

Changes in Lp-PLA2 activity in secondary prevention predict coronary events and treatment effect by pravastatin in long term intervention with pravastatin in ischemic disease (LIPID) TrialWhite HD, Simes J, Barnes, E et al. Changes in Lp-PLA2 activity in secondary prevention predict coronary events and treatment effect by pravastatin in long term intervention with pravastatin in ischemic disease (LIPID) Trial. Circulation, abstract 14857, AHA 2011

Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2Saougos VG, Tambaki AP, Kalogirou M, Kostapanos M, Gazi IF, Wolfert RL, Elisaf M, Tselepis AD. Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2. Arterioscler Thromb Vasc Biol. 2007; 27: 2236-43.

Effects of Atorvastatin Versus Other Statins on Fasting and Postprandial C-Reactive Protein and Lipoprotein-Associated Phospholipase A2 in Patients With Coronary Heart Disease Versus Control SubjectsSchaefer EJ, McNamara JR, Asztalos BF, Tayler T, Daly JA, Gleason JL, Seman LJ, Ferrari A, Rubenstein JJ. Effects of Atorvastatin Versus Other Statins on Fasting and Postprandial C-Reactive Protein and Lipoprotein-Associated Phospholipase A2 in Patients With Coronary Heart Disease Versus Control Subjects. Am J Cardiol. 2005; 95: 1025-32.

Effects of Extended-Release Niacin on Lipoprotein Particle Size, Distribution, and Inflammatory Markers in Patients With Coronary Artery DiseaseKuvin JT, Dave DM, Sliney KA, Mooney P, Patel AR, Kimmelstiel CD, Karas RH. Effects of Extended-Release Niacin on Lipoprotein Particle Size, Distribution, and Inflammatory Markers in Patients With Coronary Artery Disease. Am J Cardiol. 2006; 98: 743-5.

Cardiovascular Events With Increased Lipoprotein-Associated Phospholipase A2 and Low High-Density Lipoprotein-Cholesterol. The Veterans Affairs HDL Intervention Trial.Robins SJ, Collins D, JJ, Bloomfield HE, Asztalos BF. Cardiovascular Events With Increased Lipoprotein-Associated Phospholipase A2 and Low High-Density Lipoprotein-Cholesterol. The Veterans Affairs HDL Intervention Trial. Arterioscler Thromb Vasc Biol. 2008; 28(6): 1172-8.

Changes in Lp-PLA2 activity in secondary prevention predict coronary events and treatment effect by pravastatin in long term intervention with pravastatin in ischemic disease (LIPID) TrialWhite HD, Simes J, Barnes, E et al. Changes in Lp-PLA2 activity in secondary prevention predict coronary events and treatment effect by pravastatin in long term intervention with pravastatin in ischemic disease (LIPID) Trial. Circulation, abstract 14857, AHA 2011

Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2Saougos VG, Tambaki AP, Kalogirou M, Kostapanos M, Gazi IF, Wolfert RL, Elisaf M, Tselepis AD. Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2. Arterioscler Thromb Vasc Biol. 2007; 27: 2236-43.

Effects of Atorvastatin Versus Other Statins on Fasting and Postprandial C-Reactive Protein and Lipoprotein-Associated Phospholipase A2 in Patients With Coronary Heart Disease Versus Control SubjectsSchaefer EJ, McNamara JR, Asztalos BF, Tayler T, Daly JA, Gleason JL, Seman LJ, Ferrari A, Rubenstein JJ. Effects of Atorvastatin Versus Other Statins on Fasting and Postprandial C-Reactive Protein and Lipoprotein-Associated Phospholipase A2 in Patients With Coronary Heart Disease Versus Control Subjects. Am J Cardiol. 2005; 95: 1025-32.

Effects of Extended-Release Niacin on Lipoprotein Particle Size, Distribution, and Inflammatory Markers in Patients With Coronary Artery DiseaseKuvin JT, Dave DM, Sliney KA, Mooney P, Patel AR, Kimmelstiel CD, Karas RH. Effects of Extended-Release Niacin on Lipoprotein Particle Size, Distribution, and Inflammatory Markers in Patients With Coronary Artery Disease. Am J Cardiol. 2006; 98: 743-5.

Cardiovascular Events With Increased Lipoprotein-Associated Phospholipase A2 and Low High-Density Lipoprotein-Cholesterol. The Veterans Affairs HDL Intervention Trial.Robins SJ, Collins D, JJ, Bloomfield HE, Asztalos BF. Cardiovascular Events With Increased Lipoprotein-Associated Phospholipase A2 and Low High-Density Lipoprotein-Cholesterol. The Veterans Affairs HDL Intervention Trial. Arterioscler Thromb Vasc Biol. 2008; 28(6): 1172-8.

Changes in Lp-PLA2 activity in secondary prevention predict coronary events and treatment effect by pravastatin in long term intervention with pravastatin in ischemic disease (LIPID) TrialWhite HD, Simes J, Barnes, E et al. Changes in Lp-PLA2 activity in secondary prevention predict coronary events and treatment effect by pravastatin in long term intervention with pravastatin in ischemic disease (LIPID) Trial. Circulation, abstract 14857, AHA 2011

Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2Saougos VG, Tambaki AP, Kalogirou M, Kostapanos M, Gazi IF, Wolfert RL, Elisaf M, Tselepis AD. Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2. Arterioscler Thromb Vasc Biol. 2007; 27: 2236-43.

Effects of Atorvastatin Versus Other Statins on Fasting and Postprandial C-Reactive Protein and Lipoprotein-Associated Phospholipase A2 in Patients With Coronary Heart Disease Versus Control SubjectsSchaefer EJ, McNamara JR, Asztalos BF, Tayler T, Daly JA, Gleason JL, Seman LJ, Ferrari A, Rubenstein JJ. Effects of Atorvastatin Versus Other Statins on Fasting and Postprandial C-Reactive Protein and Lipoprotein-Associated Phospholipase A2 in Patients With Coronary Heart Disease Versus Control Subjects. Am J Cardiol. 2005; 95: 1025-32.

Effects of Extended-Release Niacin on Lipoprotein Particle Size, Distribution, and Inflammatory Markers in Patients With Coronary Artery DiseaseKuvin JT, Dave DM, Sliney KA, Mooney P, Patel AR, Kimmelstiel CD, Karas RH. Effects of Extended-Release Niacin on Lipoprotein Particle Size, Distribution, and Inflammatory Markers in Patients With Coronary Artery Disease. Am J Cardiol. 2006; 98: 743-5.

 

 

 

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A model approach

Larry H. Bernstein, MD

Executive Summary:

Sepsis is the most costly diagnosis in hospitalized patients and carries a high financial risk as a comorbidity and payment penalty under the new severity of illness CMS reimbursement guidelines as a patient safety hazard for failure to diagnose in a timely manner.  We carried out two studies of the early recognition of sepsis and related diseases in patients seen in the emergency department related to admission to the intensive care unit (ICU)(New YorkMethodistHospital) under the leadership of Lawrence Melniker, MD, Chairman of the Pharmacy and Therapeutics Committee.  The widely used SIRS criteria and the C-reactive protein, a long established acute phase protein, are each by themselves insufficient because of the low false negative rate of the former and the skewness and long tail of the latter related to uncurtailed noise from inconsequential inflammatory disease.  Using the elevated neutrophil count and left shift has proved to be elusive as well.  We and many others have established the validity of the European studies showing a marked benefit from using the procalcitonin (PCT, Brahms), and we propose to seize on the opportunity to calibrate the measurement of granulocyte maturation to the PCT.  The study would have to be carried out on a Sysmex instrument for accuracy and ease of use.  The Sysmex IG parameter is a measure of immature granulocyte counts and includes metamyelocytes, myelocytes and promyelocytes.

Background Study

Neutrophils thought to play a significant role in the early microvascular changes, are thought to be a key factor in the evolution of organ failure in the pathogenesis of severe sepsis and septic shock.  The mechanism of action of any drug or combination antibiotic combination therapy could potentially influence IG responses so that IG may be a useful way to monitor responses to therapy and disease progression by a simple, widely used hemocytometer that incorporates flow cytometry for cell identification.

An evaluation of the diagnostic performance of the Sysmex IG parameter and the procalcitonin (PCT, Brahms) assays when compared to existing practices and treatment decision guidelines is proposed following the establishment of a validated of a critical-decision cutoff for patients over 6 years old of 2.8% +0.2%.  Statistically significant numbers of samples representing the following patient groups would be assessed:

Group 1: Patients presenting to ICU with suspected Infection, SIRS (Systemic Inflammatory Response Syndrome, or severe sepsis, who are subjected to standard clinical and diagnostic investigation and do not fulfill criteria that warrant treatment with  antibiotic for the assessed state.

Group 2: Patients presenting to ICU with suspected Infection, SIRS (Systemic Inflammatory Response Syndrome, or severe sepsis, who are subjected to standard clinical and diagnostic investigation and are placed on antibiotic therapy (Infection) as a result of the investigation.

Group 3: Patients presenting to ICU with suspected Infection, SIRS (Systemic Inflammatory Response Syndrome, or severe sepsis, who are subjected to standard clinical and diagnostic investigation and are classified as having SIRS (Systemic Inflammatory Response Syndrome according to the equivalent of New York Methodist Hospital classification of SEPSIS (based on a modified Xigris (discontinue by Lilly) screening criteria, irrespective of the treatment option followed.

Group 4: Patients presenting to ICU with suspected Infection, SIRS (Systemic Inflammatory Response Syndrome, or severe sepsis, who are subjected to standard clinical and diagnostic investigation and have evidence of organ failure (New York Methodist Hospital classification of SEVERE SEPSIS; Xigris screening criteria for ACUTE ORGAN DYSFUNCTION.)

Diagnostic performance of both the Sysmex IG parameter and the procalcitonin (PCT, Brahms) assays are to be assessed as tools for sub-classification according to existing practices.

The ability of the IG parameter to detect the myeloid response associated prior to and increased with the onset of microvascular damage will be assessed. The potential to detect the IG response to predict progression towards multiple organ dysfunction could be an indication to initiate pharmacological therapy at a stage prior to significant evidence of organ failure.

The potential to use the IG parameter as a tool for monitoring responses to antibiotic and single or combination therapy could be assessed if the increase in IG shows good diagnostic performance alone or in combination as a necessary feature for decision-making.

 

SCREENING PATIENTS FOR SEVERE SEPSIS

 

http://www.xigris.com/140-screening-guide.jsp

 

GROUP 2: INFECTION–Does your patient have one or more of the following infection criteria?

  • Documented or Suspected–Does the patient have positive culture results (from blood, sputum, urine, etc.)?
  • Anti-Infective Therapy–Is the patient receiving antibiotic, antifungal, or other anti-infective therapy?
  • Pneumonia–Is there documentation of pneumonia (x-ray, etc.)?
  • WBCs–Have WBCs been found in normally sterile fl uid (urine, CSF, etc.)?
  • Perforated Viscus–Does the patient have perforated hollow organ (bowel)?
  • GROUP 3: SIRS-Does your patient have two or more of the following SIRS criteria?
  • Temperature–Is the patient’s temperature > 38°C (> 100.4°F) or < 36°C (< 96.8°F)?
  • Heart Rate–Is the patient’s heart rate > 90 bpm?
  • Respiratory Rate–Is the patient’s respiratory rate > 20 breaths/min?
  • WBC Count–Is the patient’s WBC count > 12,000/mm3, < 4000/mm3, absolute neutrophil count > 11,000/mm3, or are there > 2.8% immature granulocytes (myelocytes and metamyelocytes) discounting 10% band neutrophils and the less mature promyelocytes for left shift?
  • GROUP 4: ACUTE ORGAN DYSFUNCTION-Does your patient have one or more of the following organ dysfunction critera?
  • Cardiovascular–Does the patient have a systolic BP ≤ 90 mmHg or mean arterial pressure ≤ 70 mmHg (for at least 1 hour despite fl uid resuscitation) or require vasopressor support?
  • Respiratory–Does the patient have a PaO2/FiO2 ratio ≤ 250, PEEP > 7.5 or require mechanical ventilation?
  • Renal–Does the patient have low urine output (eg, <0.5 mL/kg/hr for 1 hour despite adequate fl uid rescuscitation),
  • increased creatinine (>50% increase from baseline) or require acute dialysis?
  • Hematologic–Does the patient have a low platelet count (< 100,000/mm3) or PT/PTT > upper limit of normal?
  • Metabolic–Does the patient have a low pH with high lactate (eg, pH < 7.30 and plasma lactate > upper limit of normal?
  • Hepatic–Are the patient’s liver enzymes > 2x upper limit of normal?
  • CNS-Does the patient have altered consciousness or reduced Glasgow Coma Score?

Guidelines For Management

Sepsis, Severe Sepsis, and Septic Shock

A. Definitions

Sepsis

Presence or Suspicion of infection and one or more of the following conditions

  • Fever (core temperature >38.3°C)
  • Hypothermia (core temperature <36°C)
  • Heart rate >90/min or >2 SD above the normal value for age
  • Tachypnea > 20/min or >2 SD above the normal value for age
  • Altered mental status
  • Leukocytosis (WBC count >12,000/µL)
  • Leukopenia (WBC count <4000/µL)
  • Neutrophilia as defined above
  • Normal WBC count with >2.8% immature granulocytes (IG)

 

Severe Sepsis

Sepsis and at least one New Organ Dysfunction

Organ dysfunction variables:

  • Altered level of consciousness or reduced Glasgow coma score
  • Arterial hypoxemia (PaO2/FIO2 <300)
  • Acute oliguria – urine output <0.5 mL/kg/hr)
  • Creatinine > 2.0 mg/dL or > 50% increase from baseline
  • Coagulation abnormalities (INR >1.5 or aPTT >60 secs)
  • Thrombocytopenia (Platelet count <100,000/µL)
  • Hyperbilirubinemia (Plasma total bilirubin > 2.0 mg/dL or 35 mmol/L)

 

Tissue perfusion variables:

  • Hyperlactatemia (>2 mmol/L)
  • Metabolic acidosis  ( pH < 7.30)

 

Hemodynamic variables:

  • Transient arterial hypotension (SBP <90, MAP <70, or SBP decrease >40 mm Hg from baseline) (Hypotension corrected with adequate volume resuscitation)

 

Septic Shock

Severe Sepsis and Persistent Arterial Hypotension

Screening Tool for Sepsis

Emergency Department, Med-Surg Floors, and Critical Care Units

 

1. Is the patient’s history suggestive of a NEW infection?                                                             ___ Yes ___No

 

[Check any that apply]

   
Pneumonia or Empyema

(  )

Skin/soft tissue infection

(  )

Urinary tract infection

(  )

Wound infection

(  )

Acute abdominal infection

(  )

Bone/joint infection

(  )

Meningitis

(  )

Bloodstream catheter

(  )

Endocarditis

(  )

Implantable device

(  )

Other

(  )

   

           

2. Are any two of the following signs, symptoms, or findings of infection

*both* – Present and New – to the patient?                                                                                    ___ Yes ___No

 

[Check any that apply]

     
Hyperthermia

> 38.3 °C (101.0 oF)

Hypothermia

< 36 °C     (96.8°F)

(  )

(  )

Leukocytosis

(WBC count >12,000/µL)

Leukopenia

(WBC count <4000/µL)

(  )

(  )

Tachycardia > 90 bpm

Tachypnea > 20 bpm

Altered mental status

(  )

(  )

(  )

Hyperglycemia

(serum glucose >120 mg/dL

– in the absence of diabetes)

(  )

If The Answer Is “YES” To BOTH Questions 1 And 2,

 

è  SUSPICION of INFECTION is Present:

 

  • Immediately obtain:
    • CBC with differential
    • Comprehensive metabolic panel
    • Procalcitonin
    • C-reative protein (CRP)
    • Lactate level
    • ABG
    • Blood cultures
    • Liver function tests
    • Coagulation profile
    • Urine analysis
    • CXR
    • Pulse co-oximetry

3. Are any of the following organ dysfunctioncriteria *both* – Present & New – in an organ remote from the site of the infection? 

___ Yes ___No

 

 

Organ Dysfunction Criteria

 

  • SBP < 90 mmHg or MAP < 65 mmHg
  • SBP decrease > 40 mm Hg from baseline
  • Bilateral pulmonary infiltrates with a:
New or increased O2 supplementation requirement to maintain SpO2 > 90%   OR
  • PaO2/FiO2 ratio < 300
  • Creatinine > 2.0 mg/dl (176.8 mmol/L)
  • Urine Output < 0.5 ml/kg/hour for > 2 hours
  • Bilirubin > 2 mg/dl (34.2 mmol/L)
  • Platelet count < 100,000
  • Coagulopathy (INR >1.5 or aPTT >60 secs)
  • Lactate > 2 mmol/L (18.0 mg/dl)
 

Note: the remote organ stipulation is waived in the case of bilateral pulmonary infiltrates

 

If suspicion of infection AND organ dysfunctionare present,

the patient meets the criteria for SEVERE SEPSIS

 

èInitiate severe sepsis protocol to achieve these goals <6 hrs

 

 

6-Hr Goals for Severe Sepsis
1)    Mean arterial pressure > 65 mm of Hg
2)    Urine output > 0.5 ml/kg/hr [average sized adult > 30-40 cc/hr]
3)    CVP > 8-10 mm Hg or Sonographic Signs of adequate filling pressures
4)    SVO2 > 70%

Early Goal-Directed Therapy for Severe Sepsis

[For Emergency Department / Med-Surg Floors / Critical Care Medicine settings]

 

First 6 hrs

 

  • Severe sepsis identified by screening                 Yes                  No
  • Blood cultures sent                                           Yes                  No
  • Serum lactate sent                                             Yes                 No
  • Patient hypotensive with
    • Systolic Blood Pressure <90 or                   Yes                  No
    • Mean Arterial Pressures < 65 mm of Hg     Yes                  No

0 – 1 hr Management

1)      Start fluid bolus normal saline 20 ml/kg at 500 – 1000ml over 30 minutes and re-evaluate blood pressure and urine output (expected value >0.5ml/kg/hr)

2)      Re-evaluate 10 minutes after fluid bolus

3)      If blood pressure is stabilized, continue fluids at maintenance rate [No CVP Monitoring Needed]

4)      O2 supplementation to maintain SaO2 > 90% — ventilatory support, if indicated

1 – 2 hrs Management

5)      If patient remains hypotensive [Med-Surg MUST Call for CVP Monitoring Approval]

  • ABG, if not done already
  • Measure CVP or Sonographic Signs of adequate filling pressure:                                           When possible:
    • Central Venous Catheterization with
    • Central Venous Pressure Transducer/Monitor

 

 

For CVP < 8-10 mm Hg and MAP < 65 mm Hg

(HYPOTENSION WITHOUT ADEQUATE FILLING PRESSURE)

  • Repeat fluid bolus 20 ml/kg at 500 –1000 ml over 30 minutes until:
    • Patient has CVP > 8-10 mm Hg
      • Continue fluid boluses to correct CVP > 8-10 mm Hg

OR

  • Signs of volume overload on physical examination
  • If patient is unstable
    • May start norepinephrine infusion at this time
 

For CVP > 8-10 mm Hg and MAP < 65 mm Hg

(HYPOTENSION WITH ADEQUATE FILLING PRESSURE)

  • Start norepinephrine infusion to achieve MAP >65 mm Hg

 

1 – 2 hrs Management (continued)

 

6)      Stat antibiotics (suggested agents – adjust for creatinine clearance)

 

  1. a.      Community Acquired Pneumonia  – Follow hospital protocol
  2. b.      Healthcare Associated Pneumonia – Follow hospital protocol
  3. Urinary tract infection (choose one)
    1. Ceftriaxone 1 gm IVPB (Community Acquired)

ii. Cefipime 1 gm IVPB (Hospital Acquired)

  1. Ciprofloxacin 400 mg IVPB (For PCN or Cephalosporin allergy)
  2. Suspected intra-abdominal infection (choose one)
    1. Cefipime 1 gm IVPB and Metronidazole 500 mg IVPB

ii. Ciprofloxacin 400 mg IVPB and Metronidazole 500 mg IVPB

  1. Piperacillin /Tazobactam 3.75 gm IVPB

 

 

2 – 6 hrs Management

6) Admit/Transfer the patient to Critical Care Medicine setting

7) Repeat lactate level in 4 hrs, if lactate > 4 mmol /L:                                                      Measure SVO2

8)  If SVO2 < 70 % & HCT < 30%:                                                                               Consider transfusion of PRBC to achieve HCT > 30%

9) Repeat SVO2 after optimization of CVP > 8-10 mm Hg & HCT > 30%:         Consider inotropic therapy

10) If SVO2 remains < 70%:                                                                                           Start Dobutamine infusion at 5 micrograms/kg/minute

6 –24 hrs Management [Critical Care Medicine]

 

   11) Evaluate for Relative Adrenal Insufficiency:                                                                      Send serum cortisol level and order cosyntropin test

12)While waiting for cortisol level:                                                                                   Start Decadron 4 mg IV

13) For blood sugar > 150 mg/dl:                                                                                                Start Critical Care Medicine Insulin protocol

14) Evaluate for drotrecogin alpha administration:                                                          Use Hospital protocol

15) If patient is on a ventilator, evaluate for ALI/ARDS:                                                  Start ARDS ventilator protocol in appropriative patients

16 If patient remain hypotensive and CVP > 8-10 mm Hg:                                                           Start Vasopressin infusion at 0.04 units per minute

Summary Approach to Problem

Objective: To sub-classify patients presenting to ICU into GROUPS 1-4 as described above, and to record the appropriate treatment decision (Antibiotics, and other).  Statistically significant numbers of patients representing each of the sub-groups will be included in the study.  Diagnostic performance of both the Sysmex IG parameter and the procalcitonin (PCT, Brahms) assays will be assessed as potential tools to differentiate groups 1 from 2, 2 from 3 and 3 from 4.

If the IG and/or procalcitonin tests are deemed valuable as markers of the microvascular damage which precedes multiple organ damage associated with sepsis, the potential exists to motivate for application as an index for the initiation of innovative drug therapy at an earlier stage, in an effort to prevent disease progression to multiple organ failure.  If data supports this change, the potential for monitoring responses to investigated antibiotic therapy in patients with raised IG and / or PCT values should be assessed.

Methods: A prospective, observational study from one or several large community or academically-linked hospitals following IRB requirements. A total of 1000 consecutive patients presenting to ICU with presumed infection/sepsis will be enrolled.  Clinical and diagnostic sub-classification according to groups 1-4 above have to be performed, in conjunction with a Sysmex CBC, Diff and IG, as well as a procalcitonin (PCT, Brahms) assay.

Results:  Statistically significant numbers of patients representing each of the 4 groups will be documented, and their treatment (antibiotic/combination drug) will be recorded.

Statistical assessment: At a minimum, ROC curve analysis of IG (and PCT) versus Group 1-4 classifications will be done. ROC curve analysis of IG (and PCT) versus therapy decisions will also be performed.  If successful, the capability of the parameters to monitor treatment responses will be assessed by serial measurements over time. A method of anomaly characterization developed by Gil David and Prof. Ronald Coifman of Yale University will be applied using key indicators to classify the patients such as WBC, percent neutrophils, IG, PCT, subclass 1-4, treatment, outcome (LOS in ICU, LOS, died).

Study Design:
Type study: Prospective and not interventional
Patient population: 1000 patients, admitted to ICU with suspected severe infection / SIRS / Sepsis.

Diagnostic information: Concurrent information gathered will be in accordance with Xigris Screening recommendations for severe sepsis, and theHospital guidelines for management of sepsis, severe sepsis and septic shock as described above.  Including – respiratory rate, heart rate, fever, location, primary and secondary diagnoses, APACHE score and SOFA score, antibiotic use, target therapy/other use etc.

 

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