Drop In Mean Arterial Pressure Research Articles

Haemodynamic stability during anaesthesia induction with propofol – impact of phenylephrine. A double-blind, randomised clinical trial

Background. We studied the effects of a parallel phenylephrine infusion during bispectral index guided anaesthesia in-duction with propofol on haemodynamic parameters. We hypothesised that mean ar-terial pressure and cardiac index would be better maintained in the group of patients receiving the phenylephrine infusion dur-ing induction.Methods. We studied ASA I-III patients scheduled for oncological abdominal sur-gery. Forty patients randomly received ei-ther a 0.9% NaCl or a phenylephrine (0.5 μg/kg/min) infusion during the induction of anaesthesia with propofol to a bispectral index value of 60. Mean arterial pressure, stroke volume index and systemic vascular resistance index were recorded, starting at one minute before induction for 20 min-utes, at one-minute intervals.Results. After induction of anaesthesia before intubation mean arterial pressure and stroke volume index decreased sig-nificantly compared to baseline in both groups, while the systemic vascular resist-ance index increased slightly. At the end of measurements, mean arterial pressure (66 ± 11 vs. 94 ± 14 mmHg; 0.9% NaCl vs. phenylephrine group p<0.01) and stroke volume index (34.2 ± 9.1 vs. 44.0 ± 9.7 ml/m2; 0.9% NaCl vs. phenylephrine group p<0.01) were lower in both groups in com-parison to baseline values, but were better maintained in the phenylephrine group, whereas systemic vascular resistance index was higher than at baseline (2308 ± 656 vs. 3198 ± 825 dynes s/cm5/m2; 0.9% NaCl vs. phenylephrine group p<0.01) with signifi-cant differences between groups. Conclusion. Our study shows that a con-tinuous phenylephrine infusion can atten-uate the drop in mean arterial pressure and stroke volume index during anaesthesia induction with propofol.

Abstract P110: Low Intensity Stimulation of Aortic Baroreceptors as a Potential Therapeutic Alternative for Hypertension Treatment

Carotid baroreceptor stimulation has been clinically explored for antihypertensive benefits but aortic baroreceptor modulation remains untouched for clinical translation. Published studies use large current/voltage amplitudes (10V), longer pulse widths (2 ms) or ultra-high frequencies (70-100 Hz). These are energy inefficient neuromodulation methods. Our main goal was to identity optimal nerve stimulation parameters that would provide a sustained drop in mean arterial pressure (MAP) of ~30 mmHg. We stimulated aortic depressor nerve (ADN) in spontaneously hypertensive rats (SHR, n =4) at low ranges of frequencies, pulse amplitudes and pulse widths. Under urethane anesthesia, left ADN was stimulated for 20 seconds at varying frequencies (1, 2.5 and 5 Hz) and pulse amplitudes (0.2, 0.4 and 0.6 mA) at 0.1, 0.2 or 0.5 ms pulse width. A frequency-dependent depressor response was seen at all pulse amplitudes and widths used. Lower pulse amplitudes (0.2 mA) produced ~18 mmHg MAP drop at all pulse widths tested. Higher pulse amplitude (0.4 and 0.6 mA) produced similar drop in MAP of ~34 mmHg. The return to baseline values was relatively prolonged with higher charge injection with 32 seconds at 0.2 mA (0.1 or 0.2 ms at 5 Hz, maximum effect size: -18 mmHg) versus 42 seconds at 0.4 or 0.6 mA (0.1, 0.2 or 0.5 ms at 5 Hz, maximum effect size: -34 mmHg). There was no added benefit of pulse amplitudes beyond 0.4 mA. We conclude that low intensity stimulation is an effective alternate way to neuromodulation of the ADN. This will enable low energy consumption for neuromodulation. Future studies will study impact of these parameters in conscious SHR rats.

Pneumatic Compression, But Not Exercise, Can Avoid Intradialytic Hypotension: A Randomized Trial

Background: Conventional hemodialysis (HD) is associated with dialysis-induced hypotension (DIH) and ineffective phosphate removal. As the main source of extracellular fluid removed during HD are the legs, we sought to reduce DIH and increase phosphate removal by using cycling and pneumatic compression, which would potentially provide higher venous return, preserving central blood flow and also offering more phosphate to the dialyzer. Methods: We evaluated 21 patients in a randomized crossover fashion in which each patient underwent 3 different HD: control; cycling exercise during the first 60 min; and pneumatic compression during the first 60 min. Data obtained included bioelectrical impedance, hourly blood pressure measurement, biochemical parameters, and direct quantification of phosphate through the dialysate. DIH was defined as a drop in mean arterial pressure (MAP) ≥20 mm Hg. Results: There was no difference in the ultrafiltration rate (p = 0.628), delta weight (p = 0.415), delta of total, intra and extracellular body water among the control, cycling, and pneumatic compression (p = 0.209, p = 0.348, and p = 0.467 respectively). Delta MAP was less changed by pneumatic compression when compared to control, cycling, and pneumatic compression respectively (-4.7 [-17.2, 8.2], -4.7 [-20.5, -0.2], and -2.3 [-8.1, 9.0] mm Hg; p = 0.021). DIH occurred in 43, 38, and 24% of patients in control, cycling, and pneumatic compression respectively (p = 0.014). Phosphate removal did not increase in any intervention (p = 0.486). Higher phosphate removal was dependent on ultrafiltration, pre dialysis serum phosphate, and higher parathyroid hormone. Conclusion: Pneumatic compression during the first hour of dialysis was associated with less DIH, albeit there was no effect on fluid parameters. Neither exercise nor pneumatic compression increased phosphate removal.

Mean arterial pressure drop is an independent risk factor of death in patients with HBV-related cirrhosis ascites.

In patients with cirrhosis ascites, mean arterial pressure (MAP) is a credible sign of circulatory dysfunction. There are no studies on the relationship between MAP and long-term prognosis in hepatitis B virus (HBV)-related liver cirrhosis ascites. Therefore, we assessed the association between MAP and prognosis in patients with liver cirrhosis ascites. In total, 110 patients of HBV-related liver cirrhosis ascites were prospectively followed for 5 years. After their admission, the patients underwent laboratory tests and MAP measurements. Multivariate analysis was conducted using backward stepwise Cox proportional hazards regression. Receiver operator characteristic (ROC) curves were used to confirm the best cutoff value of several baseline parameters, including MAP, for predicting death in patients with liver cirrhosis ascites. In a follow-up period of 5 years, 60 (54.5%) patients survived. MAP (OR 1.176, 95% CI 1.045 to 1.326, p=0.003) was an independent risk factor of death, together with Child-Pugh score (OR 1.204, 95% CI 1.068 to 1.357, p=0.002) and model for end-stage liver disease score (OR 1.297, 95% CI 1.198 to 1.405, p=0.000). The area under the ROC curve of MAP was 0.819 at baseline (95% CI 0.741 to 0.897, p=0.000). A baseline MAP value of ≤83.5 mmHg was an independent risk factor of death. A decrease in MAP was a valuable predictor of death in patients with HBV-related liver cirrhosis ascites. MAP may be used for determining the prognosis and exploring new treatment measures directed at optimizing the treatment of liver cirrhosis ascites.

Even Small Decreases in Blood Pressure during Conscious Sedation Affect Clinical Outcome after Stroke Thrombectomy: An Analysis of Hemodynamic Thresholds.

The adverse effects of general anesthesia in stroke thrombectomy have been attributed to intraprocedural hypotension, yet optimal hemodynamic targets remain elusive. Identifying hemodynamic thresholds from patients without exposure to general anesthesia may help separate the effect of hypotension from the effect of anesthesia in thrombectomy outcomes. Therefore, we investigated which hemodynamic parameters and targets best correlate with outcome in patients treated under sedation with monitored anesthesia care. We performed a retrospective analysis of a prospectively collected data base of patients with anterior circulation stroke who were successfully reperfused (modified TICI ≥ 2b) under monitored anesthesia care sedation from 2010 to 2015. Receiver operating characteristic curves were generated for the lowest mean arterial pressure before reperfusion, both as absolute values and relative changes from baseline. Cutoffs were tested in binary logistic regression models of poor outcome (90-day mRS > 2). Two-hundred fifty-six of 714 patients met the inclusion criteria. In a multivariable model, a ≥10% mean arterial pressure decrease from baseline had an OR for poor outcome of 4.38 (95% CI, 1.53-12.56; P < .01). Other models revealed that any mean pressure of <85 mm Hg before reperfusion had an OR for poor outcome of 2.22 (95% CI, 1.09-4.55; P = .03) and that every 10-mm Hg drop in mean arterial pressure below 100 mm Hg had an OR of 1.28 (95% CI, 1.01-1.62; P = .04). A ≥10% mean arterial pressure drop from baseline is a strong risk factor for poor outcome in a homogeneous population of patients with stroke undergoing thrombectomy under sedation. This threshold could guide hemodynamic management of patients during sedation and general anesthesia.

Effects of end-stage renal disease and dialysis modalities on blood ammonia level.

Uremia results in a characteristic breath odor (uremic fetor) which is largely due to its high ammonia content. Earlier studies have shown a strong correlation between breath ammonia and blood urea levels and a 10-fold reduction in breath ammonia after hemodialysis in patients with chronic kidney disease. Potential sources of breath ammonia include: (i) local ammonia production from hydrolysis of urea in the oropharyngeal and respiratory tracts by bacterial flora, and (ii) release of circulating blood ammonia by the lungs. While the effects of uremia and hemodialysis on breath ammonia are well known their effects on blood ammonia are unknown and were explored here. Blood samples were obtained from 23 hemodialysis patients (immediately before and after dialysis), 14 peritoneal dialysis patients, and 10 healthy controls. Blood levels of ammonia, creatinine, urea, and electrolytes were measured. No significant difference was found in baseline blood ammonia between hemodialysis, peritoneal dialysis and control groups. Hemodialysis procedure led to a significant reduction in urea concentration (P < 0.001) which was paradoxically accompanied by a modest but significant (P < 0.05) rise in blood ammonia level in 10 of the 23 patients studied. Change in blood ammonia pre- and post-hemodialysis correlated with change in serum bicarbonate levels (r = 0.61, P < 0.01). On subgroup analysis of patients who had a rise in blood ammonia levels after dialysis, there was a strong correlation with drop in mean arterial pressure (r = 0.88, P < 0.01). The nadir intradialytic systolic blood pressure trended lower in the hemodialysis patients who had a rise in blood ammonia compared to the patients who manifested a fall in blood ammonia (124 ± 8 vs. 136 ± 6 mmHg respectively, P = 0.27). Fall in blood urea following hemodialysis in ESRD patients was paradoxically accompanied by a modest rise in blood ammonia levels in 43% of the patients studied, contrasting prior reported effects of hemodialysis on breath ammonia. In this subgroup of patients, changes in blood ammonia during hemodialysis correlated with rise in blood bicarbonate and fall in mean arterial blood pressure.

The Creation of Surrogate Models for Fast Estimation of Complex Model Outcomes.

A surrogate model is a black box model that reproduces the output of another more complex model at a single time point. This is to be distinguished from the method of surrogate data, used in time series. The purpose of a surrogate is to reduce the time necessary for a computation at the cost of rigor and generality. We describe a method of constructing surrogates in the form of support vector machine (SVM) regressions for the purpose of exploring the parameter space of physiological models. Our focus is on the methodology of surrogate creation and accuracy assessment in comparison to the original model. This is done in the context of a simulation of hemorrhage in one model, “Small”, and renal denervation in another, HumMod. In both cases, the surrogate predicts the drop in mean arterial pressure following the intervention. We asked three questions concerning surrogate models: (1) how many training examples are necessary to obtain an accurate surrogate, (2) is surrogate accuracy homogeneous, and (3) how much can computation time be reduced when using a surrogate. We found the minimum training set size that would guarantee maximal accuracy was widely variable, but could be algorithmically generated. The average error for the pressure response to the protocols was -0.05±2.47 in Small, and -0.3 +/- 3.94 mmHg in HumMod. In the Small model, error grew with actual pressure drop, and in HumMod, larger pressure drops were overestimated by the surrogates. Surrogate use resulted in a 6 order of magnitude decrease in computation time. These results suggest surrogate modeling is a valuable tool for generating predictions of an integrative model’s behavior on densely sampled subsets of its parameter space.

Does intravenous induction dosing among patients undergoing gastrointestinal surgical procedures follow current recommendations: a study of contemporary practice

Study objectiveIt is recommended to correct intravenous induction doses by up to 50% for patients older than 65 years. The objectives were to determine (a) the degree to which anesthesia providers correct induction doses for age and (b) additionally adjust for American Society of Anesthesiologists physical status (ASA-PS) class (severity of illness) and (c) whether postinduction hypotension is more common among patients aged >65. DesignRetrospective chart review. SettingAcademic medical center. PatientsA total of 1869 adult patients receiving general anesthesia for GI surgical procedures from February 2013 to January 2014. MeasurementsPatients were divided into 3 age groups (age <65, 65-79, ≥80 years) and then further stratified into ASA-PS class (I/II vs III/IV). Multiple pairwise comparisons were conducted using Welch t tests for continuous variables to determine whether dosing was different for the older groups vs the younger group; separate analyses were performed within and across ASA-PS class. This approach was also used to determine differences in mean arterial pressure change in the older groups vs the younger group, whereas the rates of hypotension among different age groups were compared by Cochran-Armitage trend test. Main resultsNo significant decrease in dosing between age groups was observed for fentanyl and midazolam. For propofol, there was a significantly lower dosing for older patients: 17% for patients aged 65-79 and 29% for those aged >80, which was still in less than the recommendations. An inverse relationship was observed between propofol dosing and ASA-PS class, but no consistent relationship was noted for fentanyl and midazolam. There were a significantly larger drop in mean arterial pressure and a greater likelihood of hypotension following induction in patients aged 65-79 years and >80 years as compared with those aged <65 years. ConclusionsThis study shows that the administered dose of anesthetic induction agents is significantly higher than that recommended for patients older than 65 years. This failure to age-adjust dose may contribute to hypotensive episodes.

Sex differences on solid organ histological characteristics after brain death1.

To investigate gender differences in the evolution of the inflammatory process in rats subjected to brain death (BD). Adult Wistar rats were divided into three groups: female; ovariectomized female; and male rats. BD was induced using intracranial balloon inflation and confirmed by maximal pupil dilatation, apnea, absence of reflex, and drop of mean arterial pressure. Six hours after BD, histological evaluation was performed in lungs, heart, liver and kidneys, and levels of inflammatory proteins, estrogen, progesterone, and corticosterone were determined in plasma. In the lungs, females presented more leukocyte infiltration compared to males (p<0.01). Ovariectomized female rat lungs were more hemorrhagic compared to other groups (p<0.001). In the heart, females had higher leukocyte infiltration and tissue edema compared to males (p<0.05). In the liver and kidneys, there were no differences among groups. In female group estradiol and progesterone were sharply reduced 6 hours after BD (p<0.001) to values observed in ovariectomized females and males. Corticosterone levels were similar. Sex hormones influence the development of inflammation and the status of organs. The increased inflammation in lungs and heart of female rats might be associated with the acute reduction in female hormones triggered by BD.

Vasopressin‐Altered Glycemic Control May Lead to Metabolic Disorders of Severe Hemorrhagic Shock

Metabolic disorders associated with trauma and hemorrhage typically follow an early hyperglycemic reflex aimed at increasing brain blood glucose in the face of oxygen debt. The hyperglycemic reflex is believed to be initiated by hypoxia‐induced carotidbody stimulation via a vasopressin (VP) V1a receptor mechanism. We hypothesized that elevated circulating VP levels released in response to severe shock contribute not only to restoring blood pressure, but may also prolong altered glycemic control. Thus, we examined VP influence on glucose regulation after severe oxygen debt from hemorrhagic shock using Yorkshire cross pigs (n=29, body weight 31.1+0.3 kg). Rapid hemorrhage (30 ml/kg bloodshed over 20 minutes) was induced to cause a 50% drop in mean arterial pressure and an oxygen debt of 68+5 ml/kg. Blood glucose levels rose from 124+10 mg/dl at baseline to 174+10mg/dl after hemorrhage (p&lt;0.01), with accompanying increases in VP, epinephrine, glucagon, and insulin. Relationships between blood glucose, VP, epinephrine, glucagon, insulin, pancreatic blood flow and liver blood flow were examined. Multiple regression analysis of glycemic control from baseline through the end of hemorrhage indicated that glucose levels were strongly associated with VP and epinephrine, and inversely related to glucagon which correlated with VP (p&lt;0.01). VP and pancreatic blood flow remained negatively correlated in all phases of baseline, hemorrhage and resuscitation with exogenous VP (30 ng/kg/min i.v., n=7). Thus pancreatic blood flow was significantly lower (p&lt;0.01) with VP‐treated pigs (0.14+0.02 ml/kg/min) than in pigs that were resuscitated with normal saline where pancreatic blood flow (0.36+0.04ml/kg/min, n=10) did not further decrease. Exogenous VP during resuscitation also stimulated liver blood flow, and seemed to keep glucagon from decreasing despite the decreased pancreatic blood flow. VP did not affect insulin levels. Results suggest that VP mediates a hyperglycemic response in severe hemorrhagic shock via influence on glucagon secretion. If hyperglycemia continues beyond this acute response to hemorrhage, long‐term metabolic disorders could develop which would lead to tissue oxidative damage and contribute to trauma‐induced multisystem organ failure. Strategies for critical care management of hemorrhagic shock need to incorporate understanding of VP‐induced metabolic alterations of glycemic control.Support or Funding InformationThis project was supported by U.S. Army Medical Research and Materiel Command Congressionally Directed Medical Research Program grant #DAMD17‐03‐1‐0072. The views expressed in this abstract are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.

Feasibility and Safety of Mobilization of Patients with Extracorporeal Membrane Oxygenation - a Prospective Cohort Study

Introduction: Extracorporeal membrane oxygenation (ECMO) is used as temporary life support in patients with potential reversible respiratory or cardiac failure. Physical therapy of these critically ill patients provides many benefits including prevention of muscle atrophy and maintenance of fitness. The purpose of our study was to evaluate feasibility and safety of mobilization of patients with extracorporeal membrane oxygenation (ECMO) as part of routine intensive case unit (ICU) physical therapist (PT) practice. Methods: A total of 115 adult patients (67% male, mean age 57 years) were treated with an extracorporeal life support (ECLS) in our center. Different types of ECLS were used: va-ECMO (72), vv-ECMO (23), vv- ECCO2R (21), va-ECCO2R (9) and RVAD (7). Twelve patients (10,4%) were awake on ELCS. Mean duration on ECLS was 11 days and the most common site for arterial and venous cannulation were the femoral vessels (93,7%). Results: Over a 12-month study period every patient was at least once mobilized. During ECLS treatment, mobilization of patients was conducted every fourth day on average. In total, there were 332 PT interventions with a median duration of patient mobilization of 131 minutes. Mobilization to the edge of bed was performed during 45 PT interventions (14%), standing was reached with 22 patients (7%) and two patients (0,6%) walked down the corridor. During 263 PT interventions (79%) the patient was mobilized into an armchair. On average, blood flow declined 0,1 l/min during PT intervention. Also, a drop of mean arterial pressure (-14mmHg) and of oxygen saturation (- 6%) was observed. Reason for cancellation of PT intervention included patient's sedation (63%), reduced clinical status (20%), coma (4%), shortage of staff (4%), hemodynamic and respiratory instability (5%), agitation (3%) and others (1%). Following PT practice, bleeding occurred in 13 patients (3,9%) and low-flow-alarm was recognized in 12 patients (3,6%). In one case, PT intervention caused dislocation of an ECMO cannula and re-implantation was required. Conclusions: Mobilization of patients with ECMO is feasible and safe during PT practice. In less than 0,3% of PT interventions severe complications were observed including dislocation of an ECMO cannula. However, evidence on this topic is low and further studies of potential benefits of PT interventions in ECMO patients are required.

Automatic versus manual changeovers of norepinephrine infusion pumps in critically ill adults: a prospective controlled study.

BackgroundNorepinephrine is a key drug for treating shock but has a short half-life that requires continuous intravenous administration to maintain the constant plasma concentration needed to obtain a stable blood pressure. The small volume of the syringes used in power infusion pumps requires frequent changeovers, which can lead to norepinephrine flow interruptions responsible for hemodynamic instability. Changeovers from the nearly empty to the full syringe can be performed manually using the quick change technique (QC) or automatically using smart infusion pumps (SIP) that link two syringes. The purpose of our study was to evaluate the hypothesis that, compared to QC, SIP for norepinephrine changeovers was associated with less hemodynamic instability.MethodsAfter information of the patient or next of kin, patients receiving norepinephrine for shock were allocated to QC or SIP changeovers. QC changeovers were performed by a nurse, who started a new loaded pump when the previous syringe was nearly empty. SIP changeovers were managed automatically by SIP workstations. The primary outcome was the proportion of changeovers followed by a ≥20 % drop in mean arterial pressure (MAP).Results411 changeovers were performed, 193 in the 18 patients allocated to QC and 218 in the 32 patients allocated to SIP. Baseline patient characteristics were similar in both groups. The proportion of changeovers followed by an MAP drop ≥20 % was 12.4 % (24/193) with QC and 5.5 % (12/218) with SIP (P = 0.01). By multivariate analysis, two factors were independently associated with a significantly decreased risk of ≥20 % MAP drops during changeovers, namely, SIP (odds ratio, 0.47; 95 % confidence interval, 0.22–0.98) and norepinephrine dosage >0.5 μg/kg/min (odds ratio, 0.39; 95 % confidence interval, 0.19–0.81).ConclusionsThe risk of MAP drops ≥20 % during changeovers can be significantly diminished using SIPs instead of the QC method.Trial registration: Clinicaltrial.gov NCT 01127152

TEMPOL has limited protective effects on renal oxygenation and hemodynamics but reduces kidney damage and inflammation in a rat model of renal ischemia/reperfusion by aortic clamping

Renal ischemia-reperfusion (I/R) is a common clinical complication in critically ill patients that is associated with considerable morbidity and mortality. Renal I/R is a major cause of acute kidney injury (AKI) resulting from I/R-induced oxidative stress, sterile inflammation, and microcirculatory perfusion defects, which can be ameliorated with the superoxide scavenger TEMPOL. The most common cause of AKI in the clinical setting is aortic surgery with suprarenal aortic clamping. The protective effect of TEMPOL in aortic clamping-induced renal I/R has not been studied before. To evaluate the protective effects of TEMPOL on oxidative stress, inflammation, tissue injury, and renal hemodynamics and oxygenation in a clinically representative rat model of I/R using aortic cross-clamping. Animals (N = 24) were either sham-operated or subjected to ischemia (30 min) and 90-min reperfusion, with or without TEMPOL treatment (15 min before ischemia and during entire reperfusion phase, 200 μmol/kg/h). Systemic and renal hemodynamics, renal oxygenation, and blood gas values were determined at 15 min and 90 min of reperfusion. At 90-min reperfusion, iNOS, inflammation (IL-6, MPO), oxidative stress (MDA), and tissue damage (NGAL, L-FABP) were determined in tissue biopsies. TEMPOL administration at a cumulative dose of 400 μmol/kg conferred a protective effect on AKI in terms of reducing renal damage, inflammation, and iNOS activation. With respect to renal hemodynamics and oxygenation, TEMPOL only reduced renal vascular resistance to near-baseline levels at both reperfusion time points and partially ameliorated the I/R-induced drop microvascular partial tension of oxygen at 90 min reperfusion. Also, TEMPOL alleviated the I/R-induced metabolic acidosis. However, TEMPOL exerted no restorative effect in terms of the severely reduced mean arterial pressure, renal blood flow, and renal oxygen delivery and consumption. The renal oxygen extraction ratio remained unchanged during the 90-min reperfusion phase. Kidneys in all groups were anuric throughout the experiment. This clinically representative renal I/R model, which entails both renal I/R and hind limb I/R as opposed to the standardly used renal I/R model that employs renal artery clamping, resulted in relatively moderate direct AKI. The damage was exacerbated by the perturbed systemic hemodynamics and metabolic acidosis as a result of the hind limb I/R. TEMPOL partially intervened in the factors that led to AKI as well as renal microvascular partial tension of oxygen and metabolic acidosis. However, more effective interventions should be devised for the mean arterial pressure drop (i.e., anuria) associated with aortic clamping and for restoring other critical renal hemodynamic and oxygenation parameters in order to improve post-I/R renal function. TEMPOL is a promising compound that has been shown to protect kidneys from I/R damage, which is relevant in kidney transplantation, pancreas transplantation, and aortic aneurysm repair in kidney transplant patients. This study suggests that intervening with TEMPOL is not sufficient to ensure optimal clinical outcome in patients that have undergone aortic clamping and that more effective interventions should be investigated.

Pharmacological inhibition of the triggering receptor expressed on myeloid cells-1 limits reperfusion injury in a porcine model of myocardial infarction.

AimsLimitation of ischemia/reperfusion injury is a major therapeutic target after acute myocardial infarction (AMI). Toll‐like receptors are implicated in the inflammatory response that occurs during reperfusion. The triggering receptor expressed on myeloid cells (TREM)‐1 acts as an amplifier of the immune response triggered by toll‐like receptor engagement. We hypothesized that administration of a TREM‐1 inhibitory peptide (LR12) could limit reperfusion injury in a porcine model of AMI.Methods and resultsAMI was induced in 15 adult minipigs by a closed‐chest coronary artery occlusion‐reperfusion technique. Animals were randomized to receive LR12 or vehicle before reperfusion (LR12 n = 7, vehicle n = 8), and were monitored during 18 h.AMI altered hemodynamics and cardiac function, as illustrated by a drop of mean arterial pressure, cardiac index, cardiac power index, ejection fraction, and real‐time pressure–volume loop‐derived parameters. TREM‐1 inhibition by LR12 significantly improved these dysfunctions (P < 0.03) and limited infarct size, as assessed by lower creatine phosphokinase and troponin I concentrations (P < 0.005).Pulmonary, renal, and hepatic impairments occurred after AMI and were attenuated by LR12 administration as assessed by a better PaO2 to FiO2 ratio, a less positive fluid balance, and lower liver enzymes levels (P < 0.05).ConclusionInhibition of the TREM‐1 pathway by a synthetic peptide limited myocardial reperfusion injury in a clinically relevant porcine model of AMI.

Investigation of the Role of Multidrug Resistance Proteins (MRPs) in Vascular Homeostasis

Cellular levels of cyclic GMP (cGMP) are tightly controlled by synthetic and degradative mechanisms. Pharmacological manipulation of these processes (e.g. soluble guanylate cyclase stimulators and phosphodiesterase 5 inhibitors) augments cGMP-dependent signalling and is beneficial in treating cardiovascular disease (eg. pulmonary hypertension). An additional mechanism potentially important in the inactivation of cGMP is cellular extrusion, driven by a family of multidrug resistance proteins (MRPs). Herein, we investigated if MRPs modulate vascular reactivity, smooth muscle cell proliferation, and systemic hemodynamics. The functional reactivity of murine aortic rings and proliferation of human pulmonary artery smooth muscle cells (PASMC) were determined in the absence and presence of the MRP inhibitor MK571. Hemodynamic changes in vivo in response to MK571 were analysed acutely by bolus dosing and chronically by radiotelemetry. MK571 (1nM-50µM) caused a concentration-dependent relaxation of mouse aortic rings. In the presence of a threshold concentration of MK571 (3µM) vasorelaxant responses to NO and atrial natriuretic peptide were significantly augmented. MK571 (1nM-3µM) also caused a significant inhibition of PASMC growth. In vivo, MK571 (0.001-10mg/kg; iv.) elicited an acute, dose-dependent hypotensive activity and when delivered via the drinking water, caused a more sustained drop in mean arterial pressure (~5mmHg). These data suggest that extrusion by MRPs contributes to the dynamic equilibrium regulating intracellular levels of cGMP, and may represent a target amenable to drug intervention for the treatment of cardiovascular disease. Funded by the MRC

Dexmedetomidine and hydromorphone: a novel pain management strategy for the oncology ward setting during anti-GD2 immunotherapy for high-risk neuroblastoma in children.

Treatment of neuroblastoma with targeted immunotherapy using chimeric anti-GD2 monoclonal antibodies (ch14.18) is associated with significant pain requiring management with a high-dose opioid infusion. We present a case series of six children, for whom dexmedetomidine and hydromorphone infusions safely and effectively reduced the pain of ch14.18 therapy in the oncology ward setting. The ch14.18 infusion is administered for ≥ 10 hr over four consecutive days in each of 5 cycles. Hydromorphone (2-8 mcg.kg(-1) .hr(-1) ) and dexmedetomidine (0.1-0.6 mcg.kg(-1) .hr(-1) ) infusions were commenced 1 hr before starting ch14.18 immunotherapy and titrated to optimal clinical effect. One hour after stopping the ch14.18 infusion, dexmedetomidine was discontinued and hydromorphone weaned as tolerated. This strategy was supervised by the Acute Pain Service with strict monitoring and nursing policies. Patient charts were reviewed for evidence of side effects and quality of analgesia. Data from six patients, with median (range) age of 3.5 (2-12) years are reported. Median (range) utilization of hydromorphone was 2.9 (2.0-4.7) mcg.kg(-1) .hr(-1) , and of dexmedetomidine was 0.17 (0.10-0.20) mcg.kg(-1) .hr(-1) . A drop in mean arterial pressure ≥ 30% below baseline was identified during 30% of treatment days, but only prompted interrupting or reducing the ch14.18 infusion on 7% of treatment days; only one episode of grade 3 hypotension was recorded during this series. Hypoxemia occurred during 8% and bradycardia during 4% of treatment days. Dexmedetomidine infusion may be an effective and safe pain management adjunct to opioid therapy for the pain of ch14.18 infusion.

Hypoxia, not hypercapnia, induces cardiorespiratory failure in rats

Mechanical respiratory loads induce cardiorespiratory failure, presumably by increasing O2 demand concurrently with decreases in O2 availability (decreased PaO2). We tested the hypothesis that asphyxia alone can cause cardiorespiratory failure (“failure”) in pentobarbital-anesthetized rats. We also tested the hypothesis that hypoxia, not hypercapnia, is responsible by supplying supplemental O2 during mechanical loading in a separate group of rats. Asphyxia (mean PaO2 and PaCO2 of 43 and 69mmHg, respectively) resulted in failure, evident as a slowing of mean respiratory frequency (133–83breaths/min) and a sudden and large drop in mean arterial pressure (71–47mmHg), after 214±66min (n=16; range 117–355min). Neither respiratory drive nor heart rate decreased, indicating that failure was peripheral, not central. Of 8 rats tested after 3h of asphyxia for the presence in blood of cardiac troponin T, all were positive. In an additional 6 rats, normocapnic hypoxia (mean PaCO2 and PaO2 were 39±2.2 and 41±3.1mmHg, respectively) caused failure after an average 205min (range 181–275min), no different from that of asphyxic rats. In the 6 rats that breathed O2 during an initially moderate inspiratory resistive load, endurances exceeded 7h (failure occurring only because we increased the load after 6h) and tracheal pressure and left ventricular dP/dt were maintained despite supercarbia (PaCO2>150mmHg). Thus, asphyxia alone can induce failure, the failure is due to hypoxia, not hypercapnia, and hypercapnia has minimal effects on cardiac and respiratory muscle function in the presence of hyperoxia.

Vented Chest Seals for Prevention of Tension Pneumothorax in a Communicating Pneumothorax

BackgroundTension pneumothorax accounts for 3%–4% of combat casualties and 10% of civilian chest trauma. Air entering a wound via a communicating pneumothorax rather than by the trachea can result in respiratory arrest and death. In such cases, the Committee on Tactical Combat Casualty Care advocates the use of unvented chest seals to prevent respiratory compromise. ObjectiveA comparison of three commercially available vented chest seals was undertaken to evaluate the efficacy of tension pneumothorax prevention after seal application. MethodsA surgical thoracostomy was created and sealed by placing a shortened 10-mL syringe barrel (with plunger in place) into the wound. Tension pneumothorax was achieved via air introduction through a Cordis to a maximum volume of 50 mL/kg. A 20% drop in mean arterial pressure or a 20% increase in heart rate confirmed hemodynamic compromise. After evacuation, one of three vented chest seals (HyFin®, n = 8; Sentinel®, n = 8, SAM®, n = 8) was applied. Air was injected to a maximum of 50 mL/kg twice, followed by a 10% autologous blood infusion, and finally, a third 50 mL/kg air bolus. Survivors completed all three interventions, and a 15-min recovery period. ResultsThe introduction of 29.0 (±11.5) mL/kg of air resulted in tension physiology. All three seals effectively evacuated air and blood. Hemodynamic compromise failed to develop with a chest seal in place. ConclusionsHyFin®, SAM®, and Sentinel® vented chest seals are equally effective in evacuating blood and air in a communicating pneumothorax model. All three prevented tension pneumothorax formation after penetrating thoracic trauma.

P48: Effects of nitrite on hemodynamic parameters under hypoxic conditions

Blood loss and resuscitation after trauma are associated with decreased hematocrit and hypoxia. Previously we showed that nitric oxide (NO) supplemented resuscitation (Sobhian et al., Am. J. Surg. (2011)), despite a transient decrease in mean arterial pressure, significantly enhanced perfusion in various organs with a strong trend to improve survival. Recently nitrite was identified as a potent NO-source under hypoxia. The aim of this study was to investigate the hemodynamic effects of nitrite under hypoxic conditions in a volume replacement model in rats. Anesthetized rats were bled (0.5 min/ml) and Ringer’s solution was infused simultaneously (1.5 ml/min) to reduce hematocrit from 41 ± 2% to 20 ± 2%. Animals were randomly assigned to normoxia (NOX, PO2 > 80 mm Hg) or hypoxia (HOX, PO2 approx. 55 mm Hg). Hypoxia was induced by inhalation of nitrogen/air containing 15% O2. After 10 min of hypoxia or equal normoxic period, animals received a bolus dose of nitrite (15 μmol/kg). At given time points blood samples were taken for blood gas analysis and determination of NO–hemoglobin (NO–Hb) complexes. Hemodynamic parameters were determined by pulse wave analysis. Peripheral perfusion in the skin was analysed by laser Doppler imaging. Hypoxia led to a significant decrease in arterial pO2 (132.1 ± 7.0 vs. 58.9 ± 5.1 mm Hg) and SO2 (95.4 ± 0.4 vs. 69.1 ± 4.9%). Nitrite-derived NO assessed as NO–Hb complexes by electron paramagnetic resonance spectroscopy was 3.5 times higher in HOX compared to NOX group nitrite injection led to an immediate drop in mean arterial pressure (MAP) in both groups. While this was transient in the NOX group, in the HOX group MAP stayed significantly reduced until end ob observation (P < 0.05). In the HOX group vessel elasticity was significantly increased and vascular resistance decreased. This was associated with enhanced peripheral skin perfusion (P < 0.01). Similar to NO-supplemented resuscitation, nitrite under hypoxic conditions decreased MAP but increased peripheral perfusion. Additional studies will determine the impact on short-and long-term survival. Supported by FWF grant P21121. Supported by FWF Grant P21121.

Influence of regular endurance training on postexercise hemodynamic regulation to orthostatic challenge

Although postexercise syncope in endurance athletes is well recognized, the underlying mechanism is unknown. To determine whether endurance athletes exhibit the substantial hypotension during postexercise orthostatic stimulation, we conducted 5‐min head‐up tilt (HUT) tests before and after the 1‐hour moderate intensity cycling in young sedentary (S: n=8), endurance‐trained (E: n=8), and resistance‐trained (R: n=8) men. After the exercise the HUT‐induced vasoconstriction was significantly blunted in S and E groups. Significantly larger increase in the HUT‐induced fall of stroke volume was seen in E and R groups. Contrast to our hypothesis, endurance trained men did not exhibit a substantial drop of mean arterial pressure and/or pre‐syncope symptom during postexercise HUT despite the accumulated factors which facilitates orthostatic hypotension. This phenomenon might be explained by the greater augmentation of HUT‐induced tachycardia: the postexercise increase in tachycardia response was significantly greater in the endurance‐trained (+118% from preexercise) than those in the other groups (+45–50%). Collectively, during postexercise orthostatic challenge (at least in an early phase), endurance athletes maintain arterial pressure mainly by the enhanced tachycardia response.Grant: Nakatomi Foundation, Japan.