Robert H. Birkhahn

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

IntroductionAcute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.MethodsWe performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.ResultsModerate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.ConclusionsTwo novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.Trial registrationClinicalTrials.gov number NCT01209169.

Randomized, controlled clinical trial of point-of-care limited ultrasonography assistance of central venous cannulation: the Third Sonography Outcomes Assessment Program (SOAP-3) Trial.

Context:A 2001 Agency for Healthcare Research and Quality Evidence Report on patient safety addressed point-of-care limited ultrasonography guidance for central venous cannulation and strongly recommended real-time, dynamic guidance for all central cannulas. However, on the basis of one limited study, the report dismissed static assistance, a “quick look” with ultrasound to confirm vein location before preparing the sterile field, as unhelpful. Objective:The objective of this trial was to compare the overall success rate of central cannula placement with use of dynamic ultrasound (D), static ultrasound (S), and anatomical landmarks (LM). Design and Setting:A concealed, randomized, controlled, clinical trial conducted from September 2003 to February 2004 in a U.S. urban teaching hospital. Patients:Two-hundred one patients undergoing internal jugular vein central venous cannulation. Interventions:Patients were randomly assigned to three groups: 60 to D, 72 to S, and 69 to LM. An iLook25 SonoSite was used for all imaging. Measurements and Main Results:Cannulation success, first-attempt success, and number of attempts were noted. Other measures were vein size and clarity of LM. Results, controlled for pretest difficulty assessment, are stated as odds improvement (95% confidence interval) over LM for D and S. D had an odds 53.5 (6.6–440) times higher for success than LM. S had an odds 3 (1.3–7) times higher for success than LM. The unadjusted success rates were 98%, 82%, and 64% for D, S, and LM. For first-attempt success, D had an odds 5.8 (2.7–13) times higher for first success than LM, and S had an odds 3.4 (1.6–7.2) times higher for first success than LM. The unadjusted first-attempt success rates were 62%, 50%, and 23% for D, S, and LM. Conclusions:Ultrasound assistance was superior to LM techniques. D outperformed S but may require more training and personnel. All central cannula placement should be conducted with ultrasound assistance. The 2001 Agency for Healthcare Research and Quality Evidence Report dismissing static assistance was incorrect.

Diagnosis of Acute Aortic Dissection by D-Dimer. The International Registry of Acute Aortic Dissection Substudy on Biomarkers (IRAD-Bio) Experience

Background— D-dimer has been reported to be elevated in acute aortic dissection. Potential use as a “rule-out” marker has been suggested, but concerns remain given that it is elevated in other acute chest diseases, including pulmonary embolism and ischemic heart disease. We evaluated the diagnostic performance of D-dimer testing in a study population of patients with suspected aortic dissection. Methods and Results— In this prospective multicenter study, 220 patients with initial suspicion of having acute aortic dissection were enrolled, of whom 87 were diagnosed with acute aortic dissection and 133 with other final diagnoses, including myocardial infarction, angina, pulmonary embolism, and other uncertain diagnoses. D-dimer was markedly elevated in patients with acute aortic dissection. Analysis according to control disease, type of dissection, and time course showed that the widely used cutoff level of 500 ng/mL for ruling out pulmonary embolism also can reliably rule out aortic dissection, with a negative likelihood ratio of 0.07 throughout the first 24 hours. Conclusion— D-dimer levels may be useful in risk stratifying patients with suspected aortic dissection to rule out aortic dissection if used within the first 24 hours after symptom onset.

A prospective, multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis

Objective:To define a biomarker panel to predict organ dysfunction, shock, and in-hospital mortality in emergency department (ED) patients with suspected sepsis. Design:Prospective observational study. Setting:EDs of ten academic medical centers. Patients:There were 971 patients enrolled. Inclusion criteria: 1) ED patients age > 18; 2) suspected infection or a serum lactate level > 2.5 mmol/L; and 3) two or more systemic inflammatory response syndrome criteria. Exclusion criteria: pregnancy, do-not-resuscitate status, or cardiac arrest. Measurements and Main Results:Nine biomarkers were assayed from blood draws obtained on ED presentation. Multivariable logistic regression was used to identify an optimal combination of biomarkers to create a panel. The derived formula for weighting biomarker values was used to calculate a “sepsis score,” which was the predicted probability of the primary outcome of severe sepsis (sepsis plus organ dysfunction) within 72 hrs. We also assessed the ability of the sepsis score to predict secondary outcome measures of septic shock within 72 hrs and in-hospital mortality. The overall rates of each outcome were severe sepsis, 52%; septic shock, 39%; and in-hospital mortality 7%. Among the nine biomarkers tested, the optimal 3-marker panel was neutrophil gelatinase-associated lipocalin, protein C, and interleukin−1 receptor antagonist. The area under the curve for the accuracy of the sepsis score derived from these three biomarkers was 0.80 for severe sepsis, 0.77 for septic shock, and 0.79 for death. When included in multivariate models with clinical variables, the sepsis score remained highly significant (p < 0.001) for all the three outcomes. Conclusions:A biomarker panel of neutrophil gelatinase-associated lipocalin, interleukin-1ra, and Protein C was predictive of severe sepsis, septic shock, and death in ED patients with suspected sepsis. Further study is warranted to prospectively validate the clinical utility of these biomarkers and the sepsis score in risk-stratifying patients with suspected sepsis.

The Diagnostic Accuracy of Plasma Neutrophil Gelatinase–Associated Lipocalin in the Prediction of Acute Kidney Injury in Emergency Department Patients With Suspected Sepsis

STUDY OBJECTIVE We assess the diagnostic accuracy of plasma neutrophil gelatinase-associated lipocalin (NGAL) to predict acute kidney injury in emergency department (ED) patients with suspected sepsis. METHODS We conducted a secondary analysis of a prospective observational study of a convenience sample of patients from 10 academic medical center EDs. Inclusion criteria were adult patients aged 18 years or older, with suspected infection or a serum lactate level greater than 2.5 mmol/L; 2 or more systemic inflammatory response syndrome criteria; and a subsequent serum creatinine level obtained within 12 to 72 hours of enrollment. Exclusion criteria were pregnancy, do-not-resuscitate status, cardiac arrest, or dialysis dependency. NGAL was measured in plasma collected at ED presentation. Acute kidney injury was defined as an increase in serum creatinine measurement of greater than 0.5 mg/dL during 72 hours. RESULTS There were 661 patient enrolled, with 24 cases (3.6%) of acute kidney injury that developed within 72 hours after ED presentation. Median plasma NGAL levels were 134 ng/mL (interquartile range 57 to 277 ng/mL) in patients without acute kidney injury and 456 ng/mL (interquartile range 296 to 727 ng/mL) in patients with acute kidney injury. Plasma NGAL concentrations of greater than 150 ng/mL were 96% sensitive (95% confidence interval [CI] 79% to 100%) and 51% (95% CI 47% to 55%) specific for acute kidney injury. In comparison, to achieve equivalent sensitivity with initial serum creatinine level at ED presentation required a cutoff of 0.7 mg/dL and resulted in specificity of 17% (95% CI 14% to 20%). CONCLUSION In this preliminary investigation, increased plasma NGAL concentrations measured on presentation to the ED in patients with suspected sepsis were associated with the development of acute kidney injury. Our findings support NGAL as a promising new biomarker for acute kidney injury; however, further research is warranted.

Identifying Patients for Early Discharge: Performance of Decision Rules Among Patients with Acute Chest Pain

BACKGROUND The HEART score and North American Chest Pain Rule (NACPR) are decision rules designed to identify acute chest pain patients for early discharge without stress testing or cardiac imaging. This study compares the clinical utility of these decision rules combined with serial troponin determinations. METHODS AND RESULTS A secondary analysis was conducted of 1005 participants in the Myeloperoxidase In the Diagnosis of Acute coronary syndromes Study (MIDAS). MIDAS is a prospective observational cohort of Emergency Department (ED) patients enrolled from 18 US sites with symptoms suggestive of acute coronary syndrome (ACS). The ability to identify participants for early discharge and the sensitivity for ACS at 30 days were compared among an unstructured assessment, NACPR, and HEART score, each combined with troponin measures at 0 and 3h. ACS, defined as cardiac death, acute myocardial infarction, or unstable angina, occurred in 22% of the cohort. The unstructured assessment identified 13.5% (95% CI 11.5-16%) of participants for early discharge with 98% (95% CI 95-99%) sensitivity for ACS. The NACPR identified 4.4% (95% CI 3-6%) for early discharge with 100% (95% CI 98-100%) sensitivity for ACS. The HEART score identified 20% (95% CI 18-23%) for early discharge with 99% (95% CI 97-100%) sensitivity for ACS. The HEART score had a net reclassification improvement of 10% (95% CI 8-12%) versus unstructured assessment and 19% (95% CI 17-21%) versus NACPR. CONCLUSIONS The HEART score with 0 and 3 hour serial troponin measures identifies a substantial number of patients for early discharge while maintaining high sensitivity for ACS.

The ability of traditional vital signs and shock index to identify ruptured ectopic pregnancy

OBJECTIVE This study evaluated the correlation between vital signs and hemoperitoneum and the association between abnormal vital signs and tubal rupture. STUDY DESIGN With the use of a retrospective case-control design, the initial heart rate, systolic blood pressure, and heart rate/systolic blood pressure were correlated with respect to degree of hemoperitoneum; predictive values were calculated. RESULTS Fifty-two patients were studied (25 ruptured pregnancies and 27 unruptured ectopic pregnancies). Correlation coefficients were heart rate (r=0.50; 95% CI, 0.26-0.68), systolic blood pressure (r=-0.34; 95% CI, -0.56 to -0.08), and heart rate/systolic blood pressure (r=0.69; 95% CI, 0.51-0.81). The sensitivity for heart rate, systolic blood pressure, and heart rate/systolic blood pressure was 28%, 36%, and 72% respectively; the specificity was 96%, 96%, and 67%, respectively. CONCLUSION Normal vital signs alone are poor predictors of ruptured ectopic pregnancy; the heart rate/systolic blood pressure correlates best with the quantity of intraperitoneal hemorrhage.

Preliminary experience with the smooth muscle troponin-like protein, calponin, as a novel biomarker for diagnosing acute aortic dissection

AIMS The early diagnosis of acute aortic dissection (AD) remains challenging. We sought to determine the utility of the troponin-like protein of smooth muscle, calponin, as a diagnostic biomarker of acute AD. METHODS AND RESULTS Immunoassays against calponin (acidic, basic, and neutral isoforms) were developed and the levels were compared in a convenience sample of 59 patients with radiographically proven AD [34 males, age 59 +/- 15 (SD) years] vs. 158 patients suspected of having AD at presentation (116 males, age 63 +/- 15 years) but whose final diagnosis was not AD. Basic calponin, which is the most specific and abundant in smooth muscle, and acidic calponin, respectively, showed greater than two-fold and three-fold elevations in patients with acute AD. Diagnostic performance as determined by receiver-operating characteristics curve analysis showed that both acidic and basic calponin have the potential to detect AD in the first 24 h [respective areas under the curve (AUCs) 0.63 and 0.58], with superior performance of basic calponin (when compared with acidic) in the initial 6 h (respective AUCs 0.63 and 0.67). CONCLUSION Circulating calponin levels were elevated in acute AD compared with controls. These biomarkers have the potential for use as an early diagnostic biomarker for acute AD.

Thyrotoxic periodic paralysis and intravenous propranolol in the emergency setting

A 27-year-old male of Malaysian descent presented to the Emergency Department (ED) with rapidly progressive flaccid paralysis that quickly compromised his respiratory effort. The patient was found to have a serum potassium of 1.9 meq/L, and was diagnosed as having an acute paralytic episode secondary to thyrotoxic periodic paralysis. The paralytic attack was aborted with a combination of potassium replacement and parenteral propranolol in large doses. We report the use of a rarely described, yet possibly more effective, therapy for an acute attack of thyrotoxic periodic paralysis.

Multicenter clinical evaluation of the novel Alere™ i Influenza A&B isothermal nucleic acid amplification test.

BACKGROUND Rapid detection of influenza infection is important for patient management and timely anti-viral therapy. Rapid antigen detection tests for influenza have inferior sensitivity when compared to nucleic acid-based amplification tests. An isothermal nucleic acid amplification test that offers the potential for rapid molecular testing at the clinical point-of-care with simple equipment can improve influenza detection rates. OBJECTIVES To evaluate the performance of Alere™ i Influenza A&B isothermal nucleic acid amplification test to detect influenza A and B in comparison to viral cell culture as reference method. STUDY DESIGN A prospective, multicenter, clinical study to evaluate the clinical performance of the Alere™ i Influenza A&B assay in a point-of-care setting using prospectively enrolled specimens from both children and adults was conducted in seven sites. RESULTS In comparison with viral cell culture, the overall sensitivity and specificity of the Alere™ i Influenza A&B assay was 97.8% and 85.6% for the detection of influenza A, and 91.8% and 96.3% for the detection of influenza B, respectively. Following resolution of discrepant results by real-time RT-PCR the sensitivity and specificity of the Alere™ i Influenza A&B assay improved to 99.3% and 98.1% for influenza A, and 97.6% and 100% for influenza B, respectively. CONCLUSIONS The Alere™ i Influenza A&B isothermal nucleic acid amplification test is an ideal point-of-care test for influenza detection in children and adults due to its high sensitivity and specificity and ability to generate results within 15 min from specimen receipt.