The Effect of Positive End-Expiratory Pressure on Pulmonary Vascular Resistance Depends on Lung Recruitability in Patients with Acute Respiratory Distress Syndrome.

Rationale: A U-shaped relationship should exist between lung volume and pulmonary vascular resistance (PVR), with minimal PVR at FRC. Thus, positive end-expiratory pressure (PEEP) in patients with acute respiratory distress syndrome (ARDS) should increase PVR if it induces significant lung distension compared with recruitment. However, this has never been proved in patients. Objectives: To study the effects of PEEP on PVR according to lung recruitability, evaluated by the recruitment-to-inflation (R/I) ratio. Methods: In patients with ARDS, we measured hemodynamic (pulmonary artery catheter), echocardiographic, and ventilatory variables (including esophageal pressure) at both low PEEP and higher PEEP by 10 cm H2O. Preload responsiveness was assessed by the passive leg-raising test at high PEEP. Measurements and Main Results: We enrolled 23 patients, including 10 low recruiters (R/I <0.5) and 13 high recruiters (R/I ⩾0.5). Raising PEEP from 4 (2-5) to 14 (12-15) cm H2O increased PVR in low recruiters (from 160 [120-297] to 243 [166-380] dyn·s/cm5; P < 0.01), whereas PVR was unchanged in high recruiters (from 224 [185-289] to 235 [168-300] dyn·s/cm5; P = 0.55). Right-to-left ventricular end-diastolic area ratio simultaneously increased in low recruiters (from 0.54 [0.50-0.59] to 0.64 [0.56-0.70]; P < 0.01) while remaining stable in high recruiters (from 0.70 [0.65-0.79] to 0.68 [0.58-0.80]; P = 0.48). Raising PEEP decreased cardiac index only in preload responsive patients. Conclusions: PEEP increases PVR only when it induces significant lung distension compared with recruitment according to the R/I ratio. Tailoring PEEP on this recruitability index should mitigate its hemodynamic effects.

Impact of the timing of metformin administration on glycaemic and glucagon-like peptide-1 responses to intraduodenal glucose infusion in type 2 diabetes: a double-blind, randomised, placebo-controlled, crossover study.

AIMS/HYPOTHESIS: Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes. METHODS: Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = -60, -30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0-60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = -60 min and t = 120 min. RESULTS: There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = -60 or -30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = -60 or -30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given. CONCLUSIONS/INTERPRETATION: In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control. TRIAL REGISTRATION: www.anzctr.org.au ACTRN12621000878875 FUNDING: The study was not funded by a specific research grant.

Residual force depression is not related to positive muscle fascicle work during submaximal voluntary dorsiflexion contractions in humans.

Residual force depression (rFD) following active muscle shortening is assumed to correlate most strongly with muscle work, but this has not been tested during voluntary contractions in humans. Using dynamometry, we compared steady-state ankle joint torques (N = 16) following tibialis anterior (TA) muscle-tendon unit (MTU) lengthening and shortening to the time-matched torque during submaximal voluntary fixed-end dorsiflexion reference contractions (REF) at a matched MTU length and EMG amplitude. Ultrasound revealed significantly reduced (P < 0.001) TA fascicle shortening amplitudes during MTU lengthening without a preload over small and medium amplitudes, respectively, relative to REF. MTU lengthening with a preload over a large amplitude significantly (P < 0.001) increased fascicle shortening relative to REF, as well as stretch amplitudes relative to MTU lengthening without a preload (P = 0.001). Significant (P = 0.028) steady-state fascicle force enhancement relative to REF was observed following MTU lengthening, and was similar among MTU lengthening-hold conditions (3-5%). MTU shortening with and without a preload over small and large amplitudes significantly (P < 0.001) increased positive fascicle and MTU work relative to REF, but significant (P = 0.006) rFD was observed following MTU shortening with a preload (7-10%) only. rFD was linearly related to positive MTU work [rrm (47) = 0.48, P < 0.001], but not positive fascicle work [rrm (47) = 0.16, P = 0.277]. Our findings indicate that MTU lengthening without substantial fascicle stretch enhances steady-state force output, which might arise from less shortening-induced rFD. Our findings also indicate similar rFD following different amounts of positive fascicle/MTU work, which cautions against using work to predict rFD during submaximal voluntary contractions. KEY POINTS: Accurately predicting muscle force is challenging because active muscle shortening depresses force output. The residual force depression (rFD) that exists following active muscle shortening is commonly assumed to correlate strongly and positively with muscle work. We found that tibialis anterior muscle fascicle work and muscle-tendon unit work did not accurately predict rFD during submaximal voluntary dorsiflexion contractions. Fascicle shortening during fixed-end reference contractions also potentially induced rFD of 3-5%, which was similar to the rFD following muscle-tendon unit shortening without a preload. A higher number of active muscle fibres during shortening probably increased rFD, which suggests that motor unit recruitment during shortening might predict rFD.

Preload-Induced Switchable Adhesion.

Animals with robust attachment abilities commonly exhibit stable attachment and convenient detachment. However, achieving an efficient attachment-detachment function in bioinspired adhesives is challenging owing to the complexity and delay of actuators. In this study, a class of multilayer adhesives (MAs) comprising backing, middle, and bottom layers is proposed to realize rapid switching by only adjusting the preload. At low preload, the MAs maintain intimate contact with the substrate. By contrast, a sufficiently large preload results in significant deformation of the middle layer, causing underside buckling and reducing adhesion. By optimizing the structural parameters of the MAs, a high switching ratio (up to 136×) can be achieved under different preloads. Furthermore, the design of the MAs incorporates a film-terminated structure, which prevents the embedding of dirt particles, simplifies cleaning, and maintains the separation and uprightness of the microstructures. Consequently, the MAs demonstrate practical potential for simple and efficient transportation applications, as they achieve switchable adhesion through their structure, exhibiting a high switching ratio and fast switching.

Validation of Preload Assessment Technologies at Altitude in a Porcine Model of Hemorrhage.

INTRODUCTION: Dynamic preload assessment measures including pulse pressure variation (PPV), stroke volume variation (SVV), pleth variability index (PVI), and hypotension prediction index (HPI) have been utilized clinically to guide fluid management decisions in critically ill patients. These values aid in the balance of correcting hypotension while avoiding over-resuscitation leading to respiratory failure and increased mortality. However, these measures have not been previously validated at altitude or in those with temporary abdominal closure (TAC). METHODS: Forty-eight female swine (39 ± 2 kg) were separated into eight groups (n = 6) including all combinations of flight versus ground, hemorrhage versus no hemorrhage, and TAC versus no TAC. Flight animals underwent simulated aeromedical evacuation via an altitude chamber at 8000 ft. Hemorrhagic shock was induced via stepwise hemorrhage removing 10% blood volume in 15-min increments to a total blood loss of 40% or a mean arterial pressure of 35 mmHg. Animals were then stepwise transfused with citrated shed blood with 10% volume every 15 min back to full blood volume. PPV, SVV, PVI, and HPI were monitored every 15 min throughout the simulated aeromedical evacuation or ground control. Blood samples were collected and analyzed for serum levels of serum IL-1ß, IL-6, IL-8, and TNF-α. RESULTS: Hemorrhage groups demonstrated significant increases in PPV, SVV, PVI, and HPI at each step compared to nonhemorrhage groups. Flight increased PPV (P = 0.004) and SVV (P = 0.003) in hemorrhaged animals. TAC at ground level increased PPV (P < 0.0001), SVV (P = 0.0003), and PVI (P < 0.0001). When TAC was present during flight, PPV (P = 0.004), SVV (P = 0.003), and PVI (P < 0.0001) values were decreased suggesting a dependent effect between altitude and TAC. There were no significant differences in serum IL-1ß, IL-6, IL-8, or TNF-α concentration between injury groups. CONCLUSIONS: Based on our study, PPV and SVV are increased during flight and in the presence of TAC. Pleth variability index is slightly increased with TAC at ground level. Hypotension prediction index demonstrated no significant changes regardless of altitude or TAC status, however this measure was less reliable once the resuscitation phase was initiated. Pleth variability index may be the most useful predictor of preload during aeromedical evacuation as it is a noninvasive modality.

Myocardial strain is regulated by cardiac preload in the early stage of sepsis.

BACKGROUND: Owing to a lack of data, this study aimed to explore the effect of cardiac preload on myocardial strain in patients with sepsis. METHODS: A total of 70 patients with sepsis in intensive care unit (ICU) of a tertiary teaching hospital in China from January 2018 to July 2019 and underwent transthoracic echocardiography were enrolled. Echocardiographic data were recorded at ICU admission and 24 h later. Patients were assigned to low left ventricular end-diastolic volume index (LVEDVI) and normal LVEDVI groups. We assessed the impact of preload on myocardial strain between the groups and analyzed the correlation of echocardiographic parameters under different preload conditions. RESULTS: Thirty-seven patients (53%) had a low LVEDVI and 33 (47%) a normal LVEDVI. Those in the low LVEDVI group had a faster heart rate (121.7 vs. 95.3, p < 0.001) and required a greater degree of fluid infusion (3.67 L vs. 2.62 L, P = 0.019). The left ventricular global strain (LVGLS) (-8.60% vs. -10.80%, p = 0.001), left ventricular global circumferential strain (LVGCS) (-13.83% vs. -18.26%, p = 0.006), and right ventricular global longitudinal strain (RVGLS) (-6.9% vs. -10.60%, p = 0.001) showed significant improvements in the low LVEDVI group after fluid resuscitation. However, fluid resuscitation resulted in a significantly increased cardiac afterload value (1172.00 vs. 1487.00, p = 0.009) only in the normal LVEDVI group. Multivariate backward linear regression showed that LVEDVI changes were independently associated with myocardial strain-related improvements during fluid resuscitation. The baseline LVEDVI was significantly negatively correlated with the LVGLS and RVGLS (r = -0.44 and - 0.39, respectively) but not LVGCS. LVEDVI increases during fluid resuscitation were associated with improvements in the myocardial strain degree. CONCLUSIONS: Myocardial strain alterations were significantly influenced by the cardiac preload during fluid resuscitation in sepsis.

Head-down tilt reduces the heart rate in postural tachycardia syndrome in acute setting: a pilot study.

BACKGROUND: Reduced preload and thoracic blood volume accompany postural tachycardia syndrome (POTS). Head-down tilt (HDT) increases both preload and intrathoracic blood volume. The objective of this study was to assess the safety and efficacy of HDT in POTS in acute settings. METHODS: This retrospective study evaluated POTS patients. Analyzed data included heart rate, blood pressure, cerebral blood flow velocity (CBFv) in the middle cerebral artery, and capnography. The baseline supine hemodynamic data were compared with the data obtained at the second minute of the -10° HDT. A linear mixed-effects model was used to assess the effect of HDT on hemodynamic variables. RESULTS: The HDT was explored in seven POTS patients and an additional seven POTS patients without HDT served as controls. In the HDT arm, four POTS patients had overlapping diagnoses of myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) and one patient had comorbidity of post-acute sequelae of SARS-CoV-2 infection (PASC). HDT lowered heart rate by 10% and increased end-tidal CO2 by 8%. There was no change in other cardiovascular variables. CONCLUSIONS: In the acute setting, HDT is safe. HDT reduces the heart rate presumably by modulating baroreflex by enhancing preload and stroke volume, which in turn increases thoracic blood volume with a net effect of parasympathetic cardiovagal activation and/or sympathetic withdrawal. This pilot study provides a foundation to proceed with longitudinal studies exploring the long-term effect of repetitive HDT in conditions associated with preload failure such as POTS, ME/CSF, and PASC.

The effects of bolus isosorbide dinitrate on pulmonary hypertension with cardiopulmonary comorbidities.

Lowering mean pulmonary arterial pressure (mPAP) without reducing cardiac output is essential in treating pulmonary hypertension (PH). Isosorbide dinitrate (ISDN) potentially achieves this in post-capillary PH but can decrease cardiac output and blood pressure (BP), especially in pre-capillary PH. However, post-capillary PH and pre-capillary PH can overlap, and their clear discrimination is difficult. The aim of the study was to examine to what extent bolus ISDN injection reduces mPAP and BP, and changes mixed venous oxygen saturation (SvO2), an indicator of cardiac output in PH with various cardiopulmonary comorbidities in the context of treatment modifications. We retrospectively examined the hemodynamic effects of bolus ISDN injection in patients with PH who underwent right heart catheterization and their subsequent treatment modification. Our sample comprised 13 PH patients. In seven with pre-capillary PH, ISDN significantly lowered mPAP from the median 34 (interquartile range 32-39) to 28 (28-30) mmHg and the mean BP (mBP) from 90 (79-92) to 72 (68-87) mmHg. In six with post-capillary PH, ISDN lowered mPAP from 40 (29-44) to 27 (23-31) mmHg and mBP from 91 (87-110) to 87 (82-104) mmHg. There was a significant decrease in SvO2 from 69.8% (64.9%-78.1%) to 63.9% (60.5%-71.5%) in pre-capillary PH, but not in post-capillary PH including combined post- and pre-capillary PH and some patients showed a large increase in SvO2. In all patients showing an SvO2 increase, diuretics or hemodialysis were up-titrated or continued. Bolus ISDN injection lowered mPAP. However, in pre-capillary PH, it caused a significant decrease in SvO2 and a notable reduction in blood pressure. In post-capillary PH, including combined post- and pre-capillary PH, it clarified whether systemic preload and afterload reduction increased or decreased SvO2 in each patient, which may aid in treatment modification.

Determinants of Urine Output Using Advanced Hemodynamic Monitoring in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy.

INTRODUCTION: Low cardiac output and hypovolemia are candidate macrocirculatory mechanisms explanatory of de novo anuria in intensive care unit (ICU) patients undergoing continuous renal replacement therapy (CRRT). We aimed to determine the hemodynamic parameters and CRRT settings associated with the longitudinal course of UO during CRRT. METHODS: This is an ancillary analysis of the PRELOAD CRRT observational, single-center study (NCT03139123). Enrolled adult patients had severe acute kidney injury treated with CRRT for less than 24 h and were monitored with a calibrated continuous cardiac output monitoring device. Hemodynamics (including stroke volume index [SVI] and preload-dependence, identified by continuous cardiac index variation during postural maneuvers), net ultrafiltration (UFNET), and UO were reported 4-hourly, over 7 days. Two study groups were defined at inclusion: non-anuric participants if the cumulative 24 h UO at inclusion was ≥0.05 mL kg-1 h-1, and anuric otherwise. Quantitative data were reported by its median [interquartile range]. RESULTS: Forty-two patients (age 68 [58-76] years) were enrolled. At inclusion, 32 patients (76%) were not anuric. During follow-up, UO decreased significantly in non-anuric patients, with 25/32 (78%) progressing to anuria within 19 [10-50] hours. Mean arterial pressure (MAP) and UFNET did not significantly differ between study groups during follow-up, while SVI and preload-dependence were significantly associated with the interaction of study group and time since inclusion. Higher UFNET flow rates were significantly associated with higher systemic vascular resistances and lower cardiac output during follow-up. Multivariate analyses showed that (1) lower UO was significantly associated with lower SVI, lower MAP, and preload-independence; and (2) higher UFNET was significantly associated with lower UO. CONCLUSIONS: In ICU patients treated with CRRT, those without anuria showed a rapid loss of diuresis after CRRT initiation. Hemodynamic indicators of renal perfusion and effective volemia were the principal determinants of UO during follow-up, in relation with the hemodynamic impact of UFNET setting.

Increased preload and echocardiographic assessment of diastolic function.

AIMS: Echocardiographic diastolic parameters are used to diagnose and monitor increased left ventricular filling pressure (LVFP) and we hypothesized that increased loading conditions cause increased E/e'. Our aim was to assess the effect of preload augmentation on diastolic parameters among both healthy subjects and subjects with known cardiac disease. METHODS AND RESULTS: We included 129 subjects merged from two cohorts; one dialysis cohort (n = 47) and one infusion cohort (n = 82). Echocardiography was performed immediately before and after hemodialysis (HD) or saline infusion, under low and high loading conditions. Elevated LVFP was defined as septal E/e' ≥ 15 and/or lateral E/e' ≥ 13 at high-loading conditions. The population was divided according to elevated LVFP (n = 31) and normal LVFP (n = 98). The load difference for the population was 972 ± 460 mL, with no differences in load difference between elevated and normal LVFP (p NS). The subjects with elevated LVFP were older (63 ± 11 vs. 46 ± 16 years, p < .001), and had lower LV ejection fraction (50 ± 14 vs. 59 ± 8.1%, p < .01). After augmented preload, EDV increased in the normal LVFP group (p < .01) but remained unchanged in the elevated LVFP group (p NS). Both E and e' increased among the subjects with normal LVFP, whereas E/e' remained unchanged (∆E/e' +.1 [-.5-1.2]), p NS). Among the subjects with elevated, LVFP we observed increased E but not e', resulting in significantly increased E/e' (∆ average E/e' +2.4 [0-4.0], p < .01). CONCLUSION: Augmented preload does not seem to affect E/e' among subjects with normal LVFP, whereas E/e' seems to increase significantly among subjects with elevated LVFP.