Angiotensin II for Vasodilatory Hypotension in Patients Requiring Mechanical Circulatory Support.

Background: Patients supported on mechanical circulatory support devices experience vasodilatory hypotension due to high surface area exposure to nonbiological and non-endothelialized surfaces. Angiotensin II has been studied in general settings of vasodilatory shock, however concerns exist regarding the use of this vasopressor in patients with pre-existing cardiac failure. The objective of this study was to assess the systemic and central hemodynamic effects of angiotensin II in patients with primary cardiac or respiratory failure requiring treatment with mechanical circulatory support devices. Methods: Multicenter retrospective observational study of adults supported on a mechanical circulatory support device who received angiotensin II for vasodilatory shock. The primary outcome was the intraindividual change from baseline in mean arterial pressure (MAP) and vasopressor dosage after angiotensin II. Results: Fifty patients were included with mechanical circulatory devices that were primarily used for cardiac failure (n = 41) or respiratory failure (n = 9). At angiotensin II initiation, the norepinephrine equivalent vasopressor dosage was 0.44 (0.34, 0.64) and 0.47 (0.33, 0.73) mcg/kg/min in the cardiac and respiratory groups, respectively. In the cardiac group, MAP increased from 60 to 70 mmHg (intraindividual P < .001) in the 1 h after angiotensin II initiation and the vasopressor dosage declined by 0.04 mcg/kg/min (intraindividual P < .001). By 12 h, the vasopressor dosage declined by 0.16 mcg/kg/min (P = .001). There were no significant changes in cardiac index or mean pulmonary artery pressure throughout the 12 h following angiotensin II. In the respiratory group, similar but nonsignificant effects at 1 h on MAP (61-81 mmHg, P = .26) and vasopressor dosage (decline by 0.13 mcg/kg/min, P = .06) were observed. Conclusions: In patients requiring mechanical circulatory support for cardiac failure, angiotensin II produced beneficial systemic hemodynamic effects without negatively impacting cardiac function or pulmonary pressures. The systemic hemodynamic effects in those with respiratory failure were nonsignificant due to limited sample size.

Angiotensin II Infusion for Shock: A Multicenter Study of Postmarketing Use.

BACKGROUND: Vasodilatory shock refractory to catecholamine vasopressors and arginine vasopressin is highly morbid and responsible for significant mortality. Synthetic angiotensin II is a potent vasoconstrictor that may be suitable for use in these patients. RESEARCH QUESTION: What is the safety and effectiveness of angiotensin II and what variables are associated with a favorable hemodynamic response? STUDY DESIGN AND METHODS: We performed a multicenter, retrospective study at five tertiary medical centers in the United States. The primary end point of hemodynamic responsiveness to angiotensin II was defined as attainment of mean arterial pressure (MAP) of ≥ 65 mm Hg with a stable or reduced total vasopressor dosage 3 h after drug initiation. RESULTS: Of 270 included patients, 181 (67%) demonstrated hemodynamic responsiveness to angiotensin II. Responders showed a greater increase in MAP (+10.3 mm Hg vs +1.6 mm Hg, P < .001) and reduction in vasopressor dosage (-0.20 µg/kg/min vs +0.04 µg/kg/min; P < .001) compared with nonresponders at 3 h. Variables associated with favorable hemodynamic response included lower lactate concentration (OR 1.11; 95% CI, 1.05-1.17, P < .001) and receipt of vasopressin (OR, 6.05; 95% CI, 1.98-18.6; P = .002). In severity-adjusted multivariate analysis, hemodynamic responsiveness to angiotensin II was associated with reduced likelihood of 30-day mortality (hazard ratio, 0.50; 95% CI, 0.35-0.71; P < .001). Arrhythmias occurred in 28 patients (10%) and VTE was identified in 4 patients. INTERPRETATION: In postmarketing use for vasopressor-refractory shock, 67% of angiotensin II recipients demonstrated a favorable hemodynamic response. Patients with lower lactate concentrations and those receiving vasopressin were more likely to respond to angiotensin II. Patients who responded to angiotensin II experienced reduced mortality.

Bedside Ultrasound Reduces Diagnostic Uncertainty and Guides Resuscitation in Patients With Undifferentiated Hypotension.

OBJECTIVES: Utilization of ultrasound in the evaluation of patients with undifferentiated hypotension has been proposed in several protocols. We sought to assess the impact of an ultrasound hypotension protocol on physicians' diagnostic certainty, diagnostic ability, and treatment and resource utilization. DESIGN: Prospective observational study. SETTING: Emergency department in a single, academic tertiary care hospital. SUBJECTS: A convenience sample of patients with a systolic blood pressure less than 90 mm Hg after an initial fluid resuscitation, who lacked an obvious source of hypotension. INTERVENTIONS: An ultrasound-trained physician performed an ultrasound on each patient using a standardized hypotension protocol. Differential diagnosis and management plan was solicited from the treating physician immediately before and after the ultrasound. Blinded chart review was conducted for management and diagnosis during the emergency department and inpatient hospital stay. MEASUREMENTS AND MAIN RESULTS: The primary endpoints were the identification of an accurate cause for hypotension and change in physicians' diagnostic uncertainty. The secondary endpoints were changes in treatment plan, use of resources, and changes in disposition after performing the ultrasound. One hundred eighteen patients with a mean age of 62 years were enrolled. There was a significant 27.7% decrease in the mean aggregate complexity of diagnostic uncertainty before and after the ultrasound hypotension protocol (1.85-1.34; -0.51 [95% CI, -0.41 to -0.62]) as well as a significant increase in the absolute proportion of patients with a definitive diagnosis from 0.8% to 12.7%. Overall, the leading diagnosis after the ultrasound hypotension protocol demonstrated excellent concordance with the blinded consensus final diagnosis (Cohen k = 0.80). Twenty-nine patients (24.6%) had a significant change in the use of IV fluids, vasoactive agents, or blood products. There were also significant changes in major diagnostic imaging (30.5%), consultation (13.6%), and emergency department disposition (11.9%). CONCLUSIONS: Clinical management involving the early use of ultrasound in patients with hypotension accurately guides diagnosis, significantly reduces physicians' diagnostic uncertainty, and substantially changes management and resource utilization in the emergency department.

Furosemide Stress Test and Biomarkers for the Prediction of AKI Severity.

Clinicians have access to limited tools that predict which patients with early AKI will progress to more severe stages. In early AKI, urine output after a furosemide stress test (FST), which involves intravenous administration of furosemide (1.0 or 1.5 mg/kg), can predict the development of stage 3 AKI. We measured several AKI biomarkers in our previously published cohort of 77 patients with early AKI who received an FST and evaluated the ability of FST urine output and biomarkers to predict the development of stage 3 AKI (n=25 [32.5%]), receipt of RRT (n=11 [14.2%]), or inpatient mortality (n=16 [20.7%]). With an area under the curve (AUC)±SEM of 0.87±0.09 (P<0.0001), 2-hour urine output after FST was significantly better than each urinary biomarker tested in predicting progression to stage 3 (P<0.05). FST urine output was the only biomarker to significantly predict RRT (0.86±0.08; P=0.001). Regardless of the end point, combining FST urine output with individual biomarkers using logistic regression did not significantly improve risk stratification (ΔAUC, P>0.10 for all). When FST urine output was assessed in patients with increased biomarker levels, the AUC for progression to stage 3 improved to 0.90±0.06 and the AUC for receipt of RRT improved to 0.91±0.08. Overall, in the setting of early AKI, FST urine output outperformed biochemical biomarkers for prediction of progressive AKI, need for RRT, and inpatient mortality. Using a FST in patients with increased biomarker levels improves risk stratification, although further research is needed.

Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication.

RATIONALE: We recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest. OBJECTIVES: We now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients. METHODS: We conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test. MEASUREMENTS AND MAIN RESULTS: Urinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3 (ng/ml)(2)/1,000 was 92% (95% confidence interval [CI], 85-98%) with a negative likelihood ratio of 0.18 (95% CI, 0.06-0.33). Critically ill patients with urinary [TIMP-2]·[IGFBP7] greater than 0.3 had seven times the risk for AKI (95% CI, 4-22) compared with critically ill patients with a test result below 0.3. In a multivariate model including clinical information, urinary [TIMP-2]·[IGFBP7] remained statistically significant and a strong predictor of AKI (area under the curve, 0.70, 95% CI, 0.63-0.76 for clinical variables alone, vs. area under the curve, 0.86, 95% CI, 0.80-0.90 for clinical variables plus [TIMP-2]·[IGFBP7]). CONCLUSIONS: Urinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)(2)/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962).

Development and standardization of a furosemide stress test to predict the severity of acute kidney injury.

INTRODUCTION: In the setting of early acute kidney injury (AKI), no test has been shown to definitively predict the progression to more severe stages. METHODS: We investigated the ability of a furosemide stress test (FST) (one-time dose of 1.0 or 1.5 mg/kg depending on prior furosemide-exposure) to predict the development of AKIN Stage-III in 2 cohorts of critically ill subjects with early AKI. Cohort 1 was a retrospective cohort who received a FST in the setting of AKI in critically ill patients as part of Southern AKI Network. Cohort 2 was a prospective multicenter group of critically ill patients who received their FST in the setting of early AKI. RESULTS: We studied 77 subjects; 23 from cohort 1 and 54 from cohort 2; 25 (32.4%) met the primary endpoint of progression to AKIN-III. Subjects with progressive AKI had significantly lower urine output following FST in each of the first 6 hours (p<0.001). The area under the receiver operator characteristic curves for the total urine output over the first 2 hours following FST to predict progression to AKIN-III was 0.87 (p = 0.001). The ideal-cutoff for predicting AKI progression during the first 2 hours following FST was a urine volume of less than 200mls(100ml/hr) with a sensitivity of 87.1% and specificity 84.1%. CONCLUSIONS: The FST in subjects with early AKI serves as a novel assessment of tubular function with robust predictive capacity to identify those patients with severe and progressive AKI. Future studies to validate these findings are warranted.

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

INTRODUCTION: Acute 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. METHODS: We 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. RESULTS: Moderate 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. CONCLUSIONS: Two 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 REGISTRATION: ClinicalTrials.gov number NCT01209169.

Hemodynamic monitoring in the critical care environment.

Hemodynamic monitoring is essential to the care of the critically ill patient. In the hemodynamically unstable patient where volume status is not only difficult to determine, but excess fluid administration can lead to adverse consequences, utilizing markers that guide resuscitation can greatly affect outcomes. Several markers and devices have been developed to aid the clinician in assessing volume status with the ultimate goal of optimizing tissue oxygenation and organ perfusion. Early static measures of volume status, including pulmonary artery occlusion pressure and central venous pressure, have largely been replaced by newer dynamic measures that rely on real-time measurements of physiological parameters to calculate volume responsiveness. Technological advances have lead to the creation of invasive and noninvasive devices that guide the physician through the resuscitative process. In this manuscript, we review the physiologic rationale behind hemodynamic monitoring, define the markers of volume status and volume responsiveness, and explore the various devices and technologies available for the bedside clinician.

Hemodynamic monitoring in the critically ill: spanning the range of kidney function.

Critically ill patients often have deranged hemodynamics. Physical examination, central venous pressure, and pulmonary artery occlusion pressure ("wedge") have been shown to be unreliable at assessing volume status, volume responsiveness, and adequacy of cardiac output in critically ill patients. Thus, invasive and noninvasive cardiac output monitoring is a core feature of evaluating and managing a hemodynamically unstable patient. In this review, we discuss the various techniques and options of cardiac output assessment available to clinicians for hemodynamic monitoring in the intensive care unit. Issues related to patients with kidney disease, such as timing and location of arterial and central venous catheters and the approach to hemodynamics in patients treated by long-term dialysis also are discussed.

Neurogenic pulmonary edema: successful treatment with IV phentolamine.

Neurogenic pulmonary edema (NPE) is a clinical syndrome characterized by the acute onset of pulmonary edema following a significant CNS insult. The cause is believed to be a surge of catecholamines that results in cardiopulmonary dysfunction. Although there are myriad case reports describing CNS events that are associated with this syndrome, few studies have identified specific treatment modalities. We present a case of NPE caused by an intracranial hemorrhage from a ruptured arteriovenous malformation. We uniquely document a rise and fall of serum catecholamine levels correlating with disease activity and a dramatic clinical response to IV phentolamine.

Femoral-based central venous oxygen saturation is not a reliable substitute for subclavian/internal jugular-based central venous oxygen saturation in patients who are critically ill.

BACKGROUND: Central venous oxygen saturation (Scv(O(2))) has been used as a surrogate marker for mixed venous oxygen saturation (Sv(O(2))). Femoral venous oxygen saturation (Sfv(O(2))) is sometimes used as a substitute for Scv(O(2)). The purpose of this study is to test the hypothesis that these values can be used interchangeably in a population of patients who are critically ill. METHODS: We conducted a survey to assess the frequency of femoral line insertion during the initial treatment of patients who are critically ill. Scv(O(2)) vs Sfv(O(2)) STUDY: Patients with femoral and nonfemoral central venous catheters (CVCs) were included in this prospective study. Two sets of paired blood samples were drawn simultaneously from the femoral and nonfemoral CVCs. Blood samples were analyzed for oxygen saturation and lactate. RESULTS: One hundred and fifty physicians responded to the survey. More than one-third of the physicians insert a femoral line at least 10% of the time during the initial treatment of patients who were critically ill. Scv(O(2)) vs Sfv(O(2)) STUDY: Thirty-nine patients were enrolled. The mean Scv(O(2)) and Sfv(O(2)) were 73.1% +/- 11.6% and 69.1% +/- 12.9%, respectively (P = .002), with a mean bias of 4.0% +/- 11.2% (95% limits of agreement: -18.4% to 26.4%). The mean serum lactate from the nonfemoral and femoral CVCs was 2.84 +/- 4.0 and 2.72 +/- 3.2, respectively (P = .15). CONCLUSIONS: This study revealed a significant difference between paired samples of Scv(O(2)) and Sfv(O(2)). More than 50% of Scv(O(2)) and Sfv(O(2)) values diverged by > 5%. Sfv(O(2)) is not always a reliable substitute for Scv(O(2)) and should not routinely be used in protocols to help guide resuscitation.

Clostridium difficile colitis associated with hemolytic-uremic syndrome.

The authors report the case of a 46-year-old woman who presented with vomiting and profuse bloody diarrhea. Laboratory studies were significant for a hematocrit of 27% and lactate dehydrogenase of 5,394 U/L (5,394 U/L). Her renal function deteriorated rapidly with a peak creatinine of 12.4 mg/dL (1,096.4 micromol/L), and platelet count dropped simultaneously to a nadir of 123,000/microL (123 x 10(9)/L]. Schistocytes were observed in peripheral blood smear. Stool was positive for Clostridium difficile toxin A by enzyme immunoassay (EIA). Stool assay for Shiga-like toxin was negative by EIA, and stool cultures returned negative for Escherichia coli O157:H7 and other enteric pathogens. A diagnosis of C difficile colitis associated with hemolytic-uremic syndrome was made; the patient received plasmapheresis and recovered with no relapse after 10 months of follow-up. This is the second reported case of C difficile colitis associated with hemolytic-uremic syndrome in an adult.