Lower body negative pressure (LBNP) is a tool to study compensatory mechanisms to central hypovolemia for decades. However, the underlying hemodynamic mechanisms were mostly assessed noninvasively... Show moreLower body negative pressure (LBNP) is a tool to study compensatory mechanisms to central hypovolemia for decades. However, the underlying hemodynamic mechanisms were mostly assessed noninvasively and remain unclear. We hypothesized that incremental LBNP reduces diastolic filling and thereby affects left ventricular (LV) diastolic suction (DS). Here, we investigated the impact of graded LBNP at three different levels of seal as well as during b-adrenergic stimulation by invasive pressure-volume (PV) analysis. Eight Landrace pigs were instrumented closed-chest for PV assessment. LBNP was applied at three consecutive locations: I) cranial, 10 cm below xiphoid process; II) medial, half-way between cranial and caudal; III) caudal, at the iliac spine. Level III was repeated under dobutamine infusion. At each level, baseline measurements were followed by application of incremental LBNP of -15, -30, and -45 mmHg. LBNP induced varying degrees of preload-dependent hemodynamic changes, with cranial LBNP inducing more pronounced effects than caudal. According to the Frank???Starling mechanism, graded LBNP progressively reduced LV stroke volume (LV SV) following a decrease in LV end-diastolic volume. Negative intraventricular minimal pressures were observed during dobutamine-infusion as well as higher levels of LBNP. Of note, incremental LV negative pressures were accompanied by increasing DS volumes, derived by extrapolating the volume at zero transmural pressure, the so-called equilibrium volume (V0), related to LV SV. In conclusion, graded preload reduction via LBNP shifts the PV loop to smaller volumes and end-systolic volume below V0, which induces negative LV pressures and increases LV suction. Accordingly, NEW & NOTEWORTHY This study examined the effects of incremental lower body negative pressure (LBNP) from -15 to -45 mmHg on hemodynamic regulation using invasive pressure-volume assessment in closed-chest pigs. Graded preload reduction via LBNP induces negative left ventricular (LV) pressures while increasing LV suction and thus allowing the ventricle to eject below the equilibrium volume at the end of systole. Accordingly, LBNP-induced central hypovolemia is associated with increased diastolic suction. Show less
Respiratory distress is relatively common in infants born at or near-term, particularly in infants delivered following elective cesarean section. The pathophysiology underlying respiratory distress... Show moreRespiratory distress is relatively common in infants born at or near-term, particularly in infants delivered following elective cesarean section. The pathophysiology underlying respiratory distress at term has largely been explained by a failure to clear airway liquid, but recent physiological evidence has indicated that it results from elevated airway liquid at the onset of air-breathing. We have investigated the effect of elevated airway liquid volumes at birth on cardiorespiratory function in preterm and near-term lambs. Preterm (130 +/- 0 days gestation, term -147 days gestation; n = 12) and near-term (139 +/- 1 days gestation; n = 13) lambs were instrumented (to measure blood pressure, blood flow, and blood gas status) and, at delivery, airway liquid volumes were adjusted to mimic levels expected following vaginal delivery (Controls; similar to 7 mUkg) or elective cesarean section with no labor (elevated liquid (EL); 37 mL/kg). Lambs were delivered, mechanically ventilated, and monitored for blood gas status, oxygenation, ventilator requirements, blood flows (carotid artery and pulmonary artery), and blood pressure during the first few hours of life. Preterm and near-term EL lambs had poorer gas exchange and required greater ventilatory support to maintain adequate oxygenation. Pulmonary blood flow was reduced and carotid artery blood flow, mean arterial blood pressure, and heart rate were reduced in EL near-term but not preterm lambs. These data provide further evidence that greater airway liquid volumes at birth adversely affect newborn cardiorespiratory function, with the effects being greater in near-term newborns.NEW & NOTEWORTHY We provide evidence for adverse effects of elevated airway liquid volumes at birth on pulmonary blood flow and gas exchange in both preterm and near-term lambs, although the effects were greatest in near-term newborns. Our study is an important step toward understanding the fundamental physiology underlying the cardiorespiratory morbidity associated with near-term newborns with elevated airway liquid volumes leading to respiratory distress soon after birth. Show less
Approximately 53% of near-term newborns admitted to intensive care experience respiratory distress. These newborns are commonly delivered by cesarean section and have elevated airway liquid volumes... Show moreApproximately 53% of near-term newborns admitted to intensive care experience respiratory distress. These newborns are commonly delivered by cesarean section and have elevated airway liquid volumes at birth, which can cause respiratory morbidity. We investigated the effect of providing respiratory support with a positive end-expiratory pressure (PEEP) of 8 cmH2O on lung function in newborn rabbit kittens with elevated airway liquid volumes at birth. Near-term rabbits (30 days; term = 32 days) with airway liquid volumes that corresponded to vaginal delivery (∼7 mL/kg, control, n = 11) or cesarean section [∼37 mL/kg; elevated liquid (EL), n = 11] were mechanically ventilated (tidal volume = 8 mL/kg). The PEEP was changed after lung aeration from 0 to 8 to 0 cmH2O (control, n = 6; EL, n = 6), and in a separate group of kittens, PEEP was changed after lung aeration from 8 to 0 to 8 cmH2O (control, n = 5; EL, n = 5). Lung function (ventilator parameters, compliance, lung gas volumes, and distribution of gas within the lung) was evaluated using plethysmography and synchrotron-based phase-contrast X-ray imaging. EL kittens initially receiving 0 cmH2O PEEP had reduced functional residual capacities and lung compliance, requiring higher inflation pressures to aerate the lung compared with control kittens. Commencing ventilation with 8 cmH2O PEEP mitigated the adverse effects of EL, increasing lung compliance, functional residual capacity, and the uniformity and distribution of lung aeration, but did not normalize aeration of the distal airways. Respiratory support with PEEP supports lung function in near-term newborn rabbits with elevated airway liquid volumes at birth who are at a greater risk of suffering respiratory distress.NEW & NOTEWORTHY Term babies born by cesarean section have elevated airway liquid volumes, which predisposes them to respiratory distress. Treatments targeting molecular mechanisms to clear lung liquid are ineffective for term newborn respiratory distress. We showed that respiratory support with an end-expiratory pressure supports lung function in near-term rabbits with elevated airway liquid volumes at birth. This study provides further physiological understanding of lung function in newborns with elevated airway liquid volumes at risk of respiratory distress. Show less
Preterm newborns commonly receive intermittent positive pressure ventilation (iPPV) at birth, but the optimal approach that facilitates uniform lung aeration is unknown, particularly in a partially... Show morePreterm newborns commonly receive intermittent positive pressure ventilation (iPPV) at birth, but the optimal approach that facilitates uniform lung aeration is unknown, particularly in a partially aerated lung. As both inflation time and exogenous surfactant facilitate uniform lung aeration, we investigated whether they can improve lung aeration and lung mechanics in a partially aerated lung immediately after birth. Preterm rabbit kittens (29 days of gestation, term similar to 32 days) were delivered by caesarean section and partial lung aeration was created by intubating and mechanically ventilating the right lung. The tube was then withdrawn to ventilate both lungs using inflation times of 0.2 s or 1.0 s, with or without exogenous surfactant (200 mg/kg; Curosurf) and a tidal volume (Vt) of 8 mL/kg. Simultaneous phase contrast X-ray imaging and plethysmography were used to measure lung aeration and mechanics. Kittens ventilated with longer inflation times (1.0 s) reached their target Vt with fewer inflations, required lower inflation pressures (28.5 +/- 1.1 vs. 33.5 +/- 1.3 cmH(2)O, P = 0.01) and had higher dynamic lung compliances (0.54 +/- 0.3 vs. 0.40 +/- 0.3 cmH(2)O.mL(-1).kg(-1), P = 0.003). Surfactant increased functional residual capacity (FRC; 31.9 +/- 3.2 vs. 18.0 +/- 3.9 mL/kg, P = 0.02) and the proportion of the Vt entering the previously unaerated lung but had no effect on dynamic lung compliance. Combining early surfactant treatment with longer inflation times increases FRC levels, improves dynamic lung compliance, reduces inflation pressures and markedly increases the proportion of the lungs being ventilated during iPPV in preterm kittens with a partially aerated lung.NEW & NOTEWORTHY Preterm newborns commonly receive intermittent positive pressure ventilation (iPPV) at birth, but the optimal approach that facilitates uniform lung aeration is unknown, particularly in a partially aerated lung. Using phase contrast X-ray imaging, we showed that combining a long inflation time (1.0 s) with surfactant improved lung mechanics and aeration in the immediate newborn period. The current clinical practice of using short inflation times during iPPV might be suboptimal and a different approach is needed. Show less
Potentially, mean circulatory filling pressure (Pmcf) could aid hemodynamic management in patients admitted to the intensive care unit (ICU). However, data regarding the normal range for Pmcf do... Show morePotentially, mean circulatory filling pressure (Pmcf) could aid hemodynamic management in patients admitted to the intensive care unit (ICU). However, data regarding the normal range for Pmcf do not exist challenging its clinical use. We aimed to define the range for Pmcf for ICU patients and also calculated in what percentage of cases equilibrium between arterial blood pressure (ABP) and central venous pressure (CVP) was reached. In patients in whom no equilibrium was reached, we corrected for arterial-to-venous compliance differences. Finally, we studied the influence of patient characteristics on Pmcf. We hypothesized fluid balance, the use of vasoactive medication, being on mechanical ventilation, and the level of positive endexpiratory pressure would be positively associated with Pmcf. We retrospectively studied a cohort of 311 patients that had cardiac arrest in ICU while having active recording of ABP and CVP 1 min after death. Median Pmcf was 15 mmHg [interquartile range (IQR) 12-18]. ABP and CVP reached an equilibrium state in 52% of the cases. Correction for arterial-to-venous compliances differences resulted in a maximum alteration of 1.3 mmHg in Pmcf. Fluid balance over the last 24 h, the use of vasoactive medication, and being on mechanical ventilation were associated with a higher Pmcf. Median Pmcf was 15 mmHg (IQR 12-18). When ABP remained higher than CVP, correction for arterial-to-venous compliance differences did not result in a clinically relevant alteration of Pmcf. Pmcf was affected by factors known to alter vasomotor tone and effective circulating blood volume.NEW & NOTEWORTHY In a cohort of 311 intensive care unit (ICU) patients, median mean circulatory filling pressure (Pmcf) measured after cardiac arrest was 15 mmHg (interquartile range 12-18). In 48% of cases, arterial blood pressure remained higher than central venous pressure. but correction for arterial-to-venous compliance differences did not result in clinically relevant alterations of Pmcf. Fluid balance, use of vasopressors or inotropes, and being on mechanical ventilation were associated with a higher Pmcf. Show less
Different factors may trigger arrhythmias in diseased hearts, including fibrosis, cardiomyocyte hypertrophy, hypoxia, and inflammation. This makes it difficult to establish the relative... Show moreDifferent factors may trigger arrhythmias in diseased hearts, including fibrosis, cardiomyocyte hypertrophy, hypoxia, and inflammation. This makes it difficult to establish the relative contribution of each of them to the occurrence of arrhythmias. Accordingly, in this study, we used an in vitro model of pathological cardiac hypertrophy (PCH) to investigate its proarrhythmic features and the underlying mechanisms independent of fibrosis or other PCH-related processes. Neonatal rat ventricular cardiomyocyte (nr-vCMC) monolayers were treated with phorbol 12-myristate 13-acetate (PMA) to create an in vitro model of PCH. The electrophysiological properties of PMA-treated and control monolayers were analyzed by optical mapping at day 9 of culture. PMA treatment led to a significant increase in cell size and total protein content. It also caused a reduction in sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 level (32%) and an increase in natriuretic peptide A (42%) and alpha 1-skeletal muscle actin (34%) levels, indicating that the hypertrophic response induced by PMA was, indeed, pathological in nature. PMA-treated monolayers showed increases in action potential duration (APD) and APD dispersion, and a decrease in conduction velocity (CV; APD(30) of 306 +/- 39 vs. 148 +/- 18 ms, APD30 dispersion of 85 +/- 19 vs. 22 +/- 7 and CV of 10 +/- 4 vs. 21 +/- 2 cm/s in controls). Upon local 1-Hz stimulation, 53.6% of the PMA-treated cultures showed focal tachyarrhythmias based on triggered activity (n = 82), while the control group showed 4.3% tachyarrhythmias (n = 70). PMA-treated nr-vCMC cultures may, thus, represent a well-controllable in vitro model for testing new therapeutic interventions targeting specific aspects of hypertrophy-associated arrhythmias.NEW & NOTEWORTHY Phorbol 12-myristate 13-acetate (PMA) treatment of neonatal rat ventricular cardiomyocytes (nr-vCMCs) led to induction of many significant features of pathological cardiac hypertrophy (PCH), including action potential duration prolongation and dispersion, which provided enough time and depolarizing force for formation of early afterdepolarization (EAD)-induced focal tachyarrhythmias. PMA-treated nr-vCMCs represent a well-controllable in vitro model, which mostly resembles to moderate left ventricular hypertrophy (LVH) rather than severe LVH, in which generation of a reentry is the putative mechanism of its arrhythmias. Show less
