David A. Ludwig

Stroke volume and sympathetic responses to lower-body negative pressure reveal new insight into circulatory shock in humans.

We measured various hemodynamic responses and muscle sympathetic nerve activity (MSNA) in human subjects during a graded lower-body negative pressure (LBNP) protocol to test the hypotheses that: (1) reduced stroke volume (SV) is linearly related to increased MSNA; and (2) the onset of symptoms of impending cardiovascular collapse is associated with hypoadrenergic responses to central hypovolemia. We measured heart rates, arterial blood pressures, sympathetic neural activity (MSNA; peroneal nerve microneurography), and relative changes (% Delta) in SV (thoracic electrical bioimpedance) in 13 men during exposure to graded levels of LBNP. After a 12-min baseline data collection period, LBNP was initiated at -15 mm Hg for 12 min followed by continuous stepwise increments to -30, -45, and -60 mm Hg for 12 min each. Eight subjects completed the LBNP protocol (finishers), while the protocol was terminated prematurely during -60 mm Hg in five subjects due to onset of symptoms of cardiovascular collapse (nonfinishers). Of these subjects, we were able to record MSNA successfully throughout the LBNP protocol in four finishers and two nonfinishers. The relationship between average change in stroke volume and average change in MSNA was linear (% DeltaMSNA=464-3.6 [% DeltaSV], r2=0.98). On average, MSNA was greater in the nonfinishers at each level of LBNP compared to finishers, but peripheral resistance was lower. Our results support the hypothesis that MSNA activation is inversely related and linear to stroke volume reductions during central hypovolemia. Sympathetic withdrawal rather than hypoadrenergic function may represent a fundamental mechanism for the development of circulatory shock.

Reduction of Insulin Resistance With Effective Clearance of Hepatitis C Infection: Results From the HALT-C Trial

BACKGROUND & AIMS Hepatitis C virus (HCV) infection is associated with an increased prevalence of diabetes and insulin resistance (IR); whether this is a causal relationship has not been established. METHODS We performed a longitudinal study within the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) Trial to evaluate whether suppression of hepatitis C is associated with improvement in IR. Participants had advanced hepatic fibrosis and carried non-3 HCV genotypes (n = 96). Patients underwent 24 weeks of pegylated interferon and ribavirin therapy and were categorized into HCV clearance groups at week 20 on the basis of HCV RNA levels; null responders had <1 log(10) decline (n = 38), partial responders had >or=1 log(10) decline (n = 37) but detectable HCV RNA, and complete responders had no detectable HCV RNA (n = 21). The primary outcome was change (week 20 minus week 0) in IR by using the homeostasis model assessment (HOMA2-IR). RESULTS Adjusting only for baseline HOMA2-IR, mean HOMA2-IR differences were -2.23 (complete responders), -0.90 (partial responders), and +0.18 (null responders) (P = .036). The observed differences in mean HOMA2-IR scores were ordered in a linear fashion across response groups (P = .01). The association between HCV clearance and improvement in HOMA2-IR could not be accounted for by adiponectin or tumor necrosis factor-alpha and was independent of potential confounders including age, gender, ethnicity, body mass index, duration of infection, medications used, and fibrosis. CONCLUSIONS HCV suppression correlates with improvement in IR. These data provide further support for a role of HCV in the development of insulin resistance.

Oxygen transport characterization of a human model of progressive hemorrhage

BACKGROUND Hemorrhage continues to be a leading cause of death from trauma sustained both in combat and in the civilian setting. New models of hemorrhage may add value in both improving our understanding of the physiologic responses to severe bleeding and as platforms to develop and test new monitoring and therapeutic techniques. We examined changes in oxygen transport produced by central volume redistribution in humans using lower body negative pressure (LBNP) as a potential mimetic of hemorrhage. METHODS AND RESULTS In 20 healthy volunteers, systemic oxygen delivery and oxygen consumption, skeletal muscle oxygenation and oral mucosa perfusion were measured over increasing levels of LBNP to the point of hemodynamic decompensation. With sequential reductions in central blood volume, progressive reductions in oxygen delivery and tissue oxygenation and perfusion parameters were noted, while no changes were observed in systemic oxygen uptake or markers of anaerobic metabolism in the blood (e.g., lactate, base excess). While blood pressure decreased and heart rate increased during LBNP, these changes occurred later than the reductions in tissue oxygenation and perfusion. CONCLUSIONS These findings indicate that LBNP induces changes in oxygen transport consistent with the compensatory phase of hemorrhage, but that a frank state of shock (delivery-dependent oxygen consumption) does not occur. LBNP may therefore serve as a model to better understand a variety of compensatory physiological changes that occur during the pre-shock phase of hemorrhage in conscious humans. As such, LBNP may be a useful platform from which to develop and test new monitoring capabilities for identifying the need for intervention during the early phases of hemorrhage to prevent a patients progression to overt shock.

Radial pulse character relationships to systolic blood pressure and trauma outcomes

Background. Patient measurements that do not require monitoring equipment may be the only way to evaluate casualties in austere conditions to determine treatment andtransport priority. Objective. To test the hypothesis that palpable pulse characteristics in the radial artery would estimate systolic blood pressure (SBP) andpredict outcome in trauma patients. Methods. Data were analyzed from the medical records of 342 trauma patients ranging from 18 to 50 years of age. Prehospital data were collected by helicopter emergency medical personnel at the scene of the injury. Based on radial pulse character, patients were divided into normal (n = 313) andweak (n = 29) groups. Those whose medical records did not describe pulse characters were not considered. Differences in SBP, mortality, andmedical interventions between the radial-pulse-character groups were evaluated. Results. The SBP taken at the scene was a mean of 26 mm Hg lower in those patients with weak radial pulse characters (102 mm Hg versus 128 mm Hg). Similarly, the lowest mean SBPs recorded in the field between the normal- andweak-pulse-character groups were 112 mm Hg and99 mm Hg, respectively. Patient mortality increased with weak pulse character such that the mortality rats were 3% for the normal-pulse-character group and29% for the weak-pulse-character-group (odds ratio = 15.2). Conclusions. These preliminary data suggest that a weak radial pulse may be an acceptable method for initial rapid evaluation of trauma patients. This simple andrapid method of pulse evaluation should be considered for the triage of trauma patients in field conditions with limited instrumentation. Key words: pulse character; radial artery; systolic blood pressure; trauma; mortality.

Tracking central hypovolemia with ecg in humans: cautions for the use of heart period variability in patient monitoring.

Heart period variability (HPV) metrics have been suggested for use in medical monitoring of trauma patients. This study sought to ascertain the use of various HPV metrics in tracking central blood volume during simulated hemorrhage in individual humans. One hundred one healthy nonsmoking volunteers (58 men, 43 women) were instrumented for continuous measurement of electrocardiogram and beat-by-beat finger arterial blood pressure. Stroke volume (SV) was estimated from the arterial pulse wave and used to reflect central blood volume. Progressive lower body negative pressure (LBNP) was applied in 5-min stages until the onset of impending hemodynamic decompensation (systolic blood pressure <70 mmHg and/or presyncopal symptoms). HPV was assessed with analysis of R-to-R intervals using both linear (time and frequency domains) and nonlinear (e.g., complexity, fractality) methods. Application of increasing LBNP caused progressive reductions of SV, whereas arterial pressures changed only minimally and late. Group LBNP stage means for each HPV metric changed progressively and were strongly correlated with the mean decrease in SV (|r| ≥ 0.87). To ascertain the utility of the HPV metrics to track individual responses to central hypovolemia, the difference scores for each HPV metric were correlated at each successive LBNP level, with percentage change in SV at the subject level. This cross-correlation of difference scores revealed that none of the HPV metrics showed strong and consistent correlations (|r| ≤ 0.49) with percentage change in SV across successive LBNP levels. Although aggregate group mean values for HPV metrics are well correlated with SV changes during central hypovolemia, these metrics are less reliable when tracking individual reductions in central volume during LBNP. HPV metrics, therefore, may not be useful in monitoring hemorrhagic injuries in individual patients.

Serial Measurements of Serum NT-proBNP as Markers of Left Ventricular Systolic Function and Remodeling in Children with Heart Failure

BACKGROUND Increasing serum levels of N-terminal pro-hormone brain natriuretic peptide (NT-proBNP) are associated with worsening heart failure (HF) in adults. We determined whether changes in NT-proBNP level are associated with changes in symptoms and left ventricular (LV) systolic function and remodeling in children with HF secondary to dilated cardiomyopathy. METHODS We retrospectively examined associations between serum NT-proBNP levels and NYHA/Ross functional class, LV systolic and diastolic diameter (LVSD-z and LVDD-z), LV ejection fraction (LVEF), and LV shortening fraction (LVSF-z) using generalized linear mixed models. Fluctuation in functional class of subjects was also modeled using logistic regression and receiver operating characteristic (ROC) curves. RESULTS In 36 children (14 males), a 10-fold increase in NT-proBNP serum levels was associated (P < .001) with a 9.8% decrease in LVEF, a 3.25-unit drop in LVSF-z, a 1.53-unit increase in LVDD-z, a 2.64-unit increase in LVSD-z, and an increased odds of being in functional class III/IV (OR 85.5; 95% CI, 10.9 to 671.0). An NT-proBNP level greater than 1000 pg/mL identified children constantly or intermittently in functional class III-IV with 95% sensitivity and 80% specificity. The reliability of a single NT-proBNP value was 0.61, but the means for two and three NT-proBNP values were 0.76 and 0.82, respectively. CONCLUSIONS In children with HF, NT-proBNP is associated with cardiac symptoms and indices of LV systolic dysfunction and remodeling. NT-proBNP >1000 pg/mL identifies highly symptomatic children. Within subject serial measurements of NT-proBNP are needed for a reliable and accurate determination of disease status and/or course.

Effects of inspiratory impedance on the carotid-cardiac baroreflex response in humans.

Abstract.We were interested in a therapeutic device designed to increase carotid–cardiac baroreflex sensitivity (BRS) since high BRS is associated with a lower risk for development of hypotension in humans with experimentally–induced central hypovolemia. We hypothesized that spontaneous breathing through an impedance threshold device (ITD) designed to increase negative intrathoracic pressure during inspiration and elevate arterial blood pressure would acutely increase BRS in humans.We tested this hypothesis by measuring heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressures, and carotid-cardiac BRS in 10 female and 10 male subjects breathing through a face mask at three separate ITD conditions: (a) 6 cm H2O; (b) 12 cm H2O; and (c) a control (0 cm H2O). HR was increased (P = 0. 013) from 64 ± 3 bpm during control to 68 ± 3 bpm at 6 cm H2O ITD and 71 ± 4 bpm at 12 cm H2O ITD breathing conditions. During ITD breathing, BRS was not altered but responses were shifted to higher arterial pressures. However, SBP and DBP were elevated for both the 6 and 12 cm H2O conditions compared to the 0 cm H2O condition, but returned to control (sham) levels by 30 minutes after cessation of ITD breathing. There were no gender effects for BRS or any hemodynamic responses to breathing through the ITD. We conclude that breathing with inspiratory impedance at relatively low pressures can increase baseline arterial blood pressure, i. e., reset the operational point for SBP on the baroreflex stimulus–response relationship, in healthy subjects. This resetting of the cardiac baroreflex may represent a mechanism that allows blood pressure to increase without a reflex–mediated reduction in HR.

Expected and actual case ascertainment and treatment rates for children infected with hepatitis C in Florida and the United States: epidemiologic evidence from statewide and nationwide surveys.

OBJECTIVE To evaluate the rate of pediatric hepatitis C virus (HCV) case ascertainment relative to the estimated number of actual cases. STUDY DESIGN Data from Florida and United States health departments were used to assess pediatric HCV case ascertainment rates in Florida and nationwide. The percentage of children infected with HCV from Miami-Dade County receiving medical care by a pediatric gastroenterologist was estimated based on data obtained from physician questionnaires. RESULTS From 2000 through 2009, 2007 children were identified as having positive HCV antibody tests in Florida, only 12% of the expected number (n = 12 155). An estimated 1.6% of the expected children with HCV who tested Ab-positive (37 of 1935) were actively followed by a pediatric gastroenterologist in Miami-Dade County, Florida. Across the United States, only 4.9% of the expected cases have been identified. CONCLUSIONS The identification of children infected with HCV in the nation as a whole is grossly inadequate. Only a small fraction of cases are identified. In Florida, less than 2% of children identified receive treatment. Lack of identification and lack of treatment of children infected with HCV constitute critical public health problems. Strategies to increase awareness of HCV infection and to screen at-risk individuals could substantially improve morbidity and mortality while reducing health care costs.

Growth and Body Composition of Uninfected Children Exposed to Human Immunodeficiency Virus: Comparison with a Contemporary Cohort and United States National Standards

OBJECTIVE To compare growth and body composition of uninfected children exposed to HIV with a contemporary HIV-unexposed group and to US references. STUDY DESIGN Uninfected children exposed to HIV under 2 years were enrolled into a longitudinal observational study and unexposed children under 2 years of age in a cross-sectional evaluation. Weights, lengths, head circumferences, skinfold thicknesses, and arm and thigh circumferences were measured and adjusted for age using Centers for Disease Control and National Health and Nutrition Examination Survey standards. Uninfected children exposed to HIV were compared with an unexposed nearest-neighbor matched comparison group. Uninfected children exposed to HIV were compared by age to Centers for Disease Control standards for growth measures and National Health and Nutrition Examination Survey standards for body composition. RESULTS One hundred eleven uninfected children exposed to HIV and 82 children not exposed to HIV were evaluated. For the matched comparison for both groups, the mean age was 10 months, 59% were male, and 73% were African American. No statistical differences were found in anthropometric measurements between uninfected children who were or were not exposed to HIV. Uninfected children exposed to HIV were smaller than US standards at birth with mean (SD) weight-for-age and weight-for-length z-scores of -0.39 (1.06); P = .002 and -0.35 (1.04); P = .005, respectively. Over the first 2 years of life, there was a trend toward increasing weight-for-age z-score, length-for-age z-score, and weight-for-length z-score in uninfected children exposed to HIV. Subscapular and triceps skinfolds among uninfected children exposed to HIV were lower than national standards and there was a trend that mid-upper arm circumference decreased over time. CONCLUSIONS Growth and body composition of uninfected children who were or were not exposed to HIV were similar. Uninfected children exposed to HIV weigh less at birth and show a pattern of slightly accelerated growth in the first 2 years of life. Uninfected children exposed to HIV had less subcutaneous fat and decreasing mid-upper arm circumference over time when compared with US standards.

Is heart period variability associated with the administration of lifesaving interventions in individual prehospital trauma patients with normal standard vital signs

Objective:To determine whether heart period variability provides added value in identifying the need for lifesaving interventions (LSI) in individual trauma patients with normal standard vital signs upon early medical assessment. Design:Retrospective database review. Setting:Helicopter transport to Level 1 trauma center and first 24 hrs of in-hospital care. Patients:Prehospital trauma patients requiring helicopter transport to Level 1 trauma center. Measurements and Main Results:Heart period variability was analyzed from electrocardiographic recordings collected from 159 prehospital trauma patients with normal standard vital signs (32 LSI patients, 127 No-LSI patients). Although 13 of the electrocardiogram derived metrics demonstrated simple (i.e., univariate) discrimination between groups, at the multivariate level, only fractal dimension by curve length (FD-L) was uniquely associated with group membership (LSI vs. No-LSI, p = .0004). Whereas the area under the receiver operating characteristics curve for FD-L was 0.70, the overall correct classification rate (true positives and true negatives) of 82% was only 2% higher than the baseline prediction rate of 80% (i.e., no information except for the known proportion of overall No-LSI cases, 127 of 159 patients). Furthermore, 84% of the individual FD-L values for the LSI group were within the range of the No-LSI group. Conclusions:Only FD-L was uniquely able to distinguish patient groups based on mean values when standard vital signs were normal. However, the accuracy of FD-L in distinguishing between patients was only slightly better than the baseline prediction rate. There was also very high overlap of individual heart period variability values between groups, so many LSI patients could be incorrectly classified as not requiring an LSI if a single heart period variability value was used as a triage tool. Based on this analysis, heart period variability seems to have limited value for prediction of LSIs in prehospital trauma patients with normal standard vital signs.