High Catecholamine Research Articles

The effects of the semirecumbent position on hemodynamic status in patients on invasive mechanical ventilation: prospective randomized multivariable analysis.

IntroductionAdopting the 45° semirecumbent position in mechanically ventilated critically ill patients is recommended, as it has been shown to reduce the incidence of ventilator-associated pneumonia. Although the benefits to the respiratory system are clear, it is not known whether elevating the head of the bed results in hemodynamic instability. We examined the effect of head of bed elevation (HBE) on hemodynamic status and investigated the factors that influence mean arterial pressure (MAP) and central venous oxygen saturation (ScvO2) when patients were positioned at 0°, 30°, and 45°.MethodsTwo hundred hemodynamically stable adults on invasive mechanical ventilation admitted to a multidisciplinary surgical intensive care unit were recruited. Patients' characteristics included catecholamine and sedative doses, the original angle of head of bed elevation (HBE), the level of positive end expiratory pressure (PEEP), duration and mode of mechanical ventilation. A sequence of HBE positions (0°, 30°, and 45°) was adopted in random order, and MAP and ScvO2 were measured at each position. Patients acted as their own controls. The influence of degree of HBE and of the covariables on MAP and ScvO2 was analyzed by using liner mixed models. Additionally, uni- and multivariable logistic regression models were used to indentify risk factors for hypotension during HBE, defined as MAP <65 mmHg.ResultsChanging HBE from supine to 45° caused significant reductions in MAP (from 83.8 mmHg to 71.1 mmHg, P < 0.001) and ScvO2 (76.1% to 74.3%, P < 0.001). Multivariable modeling revealed that mode and duration of mechanical ventilation, the norepinephrine dose, and HBE had statistically significant influences. Pressure-controlled ventilation was the most influential risk factor for hypotension when HBE was 45° (odds ratio (OR) 2.33, 95% confidence interval (CI), 1.23 to 4.76, P = 0.017).ConclusionsHBE to the 45° position is associated with significant decreases in MAP and ScvO2 in mechanically ventilated patients. Pressure-controlled ventilation, higher simplified acute physiology (SAPS II) score, sedation, high catecholamine, and PEEP requirements were identified as independent risk factors for hypotension after backrest elevation. Patients at risk may need positioning at 20° to 30° to overcome the negative effects of HBE, especially in the early phase of intensive care unit admission.

New advances in beta-blocker therapy in heart failure

The use of β-blockers (BB) in heart failure (HF) has been considered a contradiction for many years. Considering HF simply as a state of inadequate systolic function, BB were contraindicated because of their negative effects on myocardial contractility. Nevertheless, evidence collected in the past years have suggested that additional mechanisms, such as compensatory neuro-humoral hyperactivation or inflammation, could participate in the pathogenesis of this complex disease. Indeed, chronic activation of the sympathetic nervous system, although initially compensating the reduced cardiac output from the failing heart, increases myocardial oxygen demand, ischemia and oxidative stress; moreover, high catecholamine levels induce peripheral vasoconstriction and increase both cardiac pre- and after-load, thus determining additional stress to the cardiac muscle (1). As a consequence of such a different view of the pathogenic mechanisms of HF, the efficacy of BB in the treatment of HF has been investigated in numerous clinical trials. Results from these trials highlighted BB as valid therapeutic tools in HF, providing rational basis for their inclusion in many HF treatment guidelines. However, controversy still exists about their use, in particular with regards to the selection of specific molecules, since BB differ in terms of adrenergic β-receptors selectivity, adjunctive effects on α-receptors, and effects on reactive oxygen species and inflammatory cytokines production. Further concerns about the heterogeneity in the response to BB, as well as the use in specific patients, are matter of debate among clinicians. In this review, we will recapitulate the pharmacological properties and the classification of BB, and the alteration of the adrenergic system occurring during HF that provide a rationale for their use; we will also focus on the possible molecular mechanisms, such as genetic polymorphisms, underlying the different efficacy of molecules belonging to this class.

Effects of terlipressin on pulmonary artery pressure in a septic cooled infant: an echocardiographic assessment

Experience with terlipressin (TP) in the neonatal field is scarce. We describe the effects of TP on pulmonary circulation, studied with echocardiography, in an asphyxiated septic cooled infant with pulmonary hypertension (PH) who developed catecholamine-resistant hypotension and exacerbation of PH shortly after the beginning of the rewarming. TP was added to norephinephine and adrenaline infusions at the dose of 0.02 mg kg(-1) every 6 h, because of refractory hypotension and oliguria. After 10 min, blood pressure dramatically and definitely increased, and urinary output was re-established after 60 min. Echocardiographic evaluation 30 min after the second bolus of TP showed unchanged velocity of the tricuspidal valve regurgitation and improved biventricular functional indexes respect to the pre-treatment assessment. TP was continued for 12 h (three doses) without significant adverse effect except for a transient increase in troponin levels. Addition of TP boluses to catecholamine infusion in our newborn was effective in increasing systemic vascular resistance without increasing pulmonary vascular resistance, successfully reversing the hemodynamics of severe PH, and suggesting a potential primary vasodilator effect on pulmonary circulation. Transient increase of troponin levels during TP treatment confirms the risk of excessive coronary vasoconstriction when TP boluses are added to high dose catecholamines.

Management of Postoperative Arrhythmias in Pediatric Patients

Post-operative arrhythmias occur commonly following pediatric cardiac surgery and can result in significant hemodynamic deterioration. Arrhythmias are more likely in the immediate post-operative period due to myocardial injury and ischemia, high catecholamine levels and electrolyte disturbances. At the same time, these arrhythmias are more likely to cause hemodynamic compromise due to the relatively tenuous cardiovascular function of patients immediately after cardiac surgery. Treatment of tachyarrhythmias often requires addressing two separate goals: termination of the arrhythmia and prevention of recurrences. These two objectives necessitate different treatment strategies in reentrant arrhythmias such as orthodromic reciprocating tachycardia, atrial fibrillation and intra-atrial reentrant tachycardia, including atrial flutter. Termination usually involves vagal maneuvers, adenosine administration, rapid pacing, or direct-current cardioversion. Prevention of recurrences, on the other hand, may require antiarrhythmic medications, although removal of central venous lines in the heart should be considered. Conversely, for automatic tachyarrhythmias, such as junctional ectopic tachycardia and ectopic atrial tachycardia, termination and prevention of recurrences usually involve similar modalities, including cooling, antiarrhythmic medications and correction of electrolyte abnormalities. Bradyarrhythmias, either sinus node dysfunction or AV block, can be treated by pacing with temporary epicardial wires in the short-term. In patients with persistent AV block for 7days, however, permanent pacemaker placement may be required.

Abstract 92: The Protective Effect of β3-Adrenergic Signaling Occurs via Differential Phosphorylation of nNOS in Cardiac Myocytes

Objective: The aim of this study is to identify the mechanisms involved in β3-adrenoreceptor (β3-AR)-dependent cardiac protection via nNOS signaling in cardiomyocytes in the setting of hypertrophy. Background: β3-AR and its downstream signaling pathways are recognized as novel modulators of heart function. Unlike β1- and β2-ARs, β3-ARs are stimulated at high catecholamine concentrations and induce negative inotropic effects, it serves as a “brake” to protect the heart from catecholamine overstimulation. We previously showed that β3-agonism restored left ventricular function, generated nitric oxide, and suppressed reactive oxygen species in mouse myocardium after pressure overload. Interestingly, cardioprotection was lost after acute nNOS inhibition and in nNOS -/- animals. Methods: Neonatal rat ventricular cardiomyocytes (NRVMs) were isolated from 2-4 day old Sprague-Dawley pups. Cells were treated with hypertrophic agents (angiotensin II, endothelin-1, and norepinephrine), the specific β3-AR agonist (BRL-37433),and phosphometic Sindbis viruses for nNOS. Results: Forty-eight hours of ET-1 (100nM) or 72 hours of NE (100μ M) treatment increased cell size and β3-AR mRNA expression vs. untreated cells. In hypertrophied cardiomyocytes, BRL (75nM) reduced cell size and induced NOS activity, nNOS phosphorylation at stimulatory site Ser1412, dephosphorylation of deactivation site Ser847, and ROS suppression. BRL-dependent NOS activity and ROS suppression were both attenuated by the nNOS inhibitor L-VNIO. NOS activity was also attenuated by phosphomemetic mutants Ser1412A (constitutively dephosphorylated) and Ser847D (constitutively phosphorylated). In addition, G i/o and Akt inhibition suppressed BRL-induced nNOS-Ser1412 phosphorylation and NOS activity. Conclusion: Our data suggest that BRL regulates β3-specific myocardial NOS activity via alterations in nNOS phosphorylation in isolated hypertrophied myocytes and failing hearts of murine animals. This is the first study to demonstrate a role for nNOS phosphorylation as a key factor in cardiac myocyte and β3-AR signaling. These results contribute significantly to our understanding of the cardiac protection.

A novel player in cellular hypertrophy: Giβγ/PI3K-dependent activation of the RacGEF TIAM-1 is required for α1-adrenoceptor induced hypertrophy in neonatal rat cardiomyocytes

Activation of α(1)-adrenoceptors (α(1)-AR) by high catecholamine levels, e.g. in heart failure, is thought to be a driving force of cardiac hypertrophy. In this context several downstream mediators and cascades have been identified to potentially play a role in cardiomyocyte hypertrophy. One of these proteins is the monomeric G protein Rac1. However, until now it is unclear how this essential G protein is activated by α(1)-AR agonists and what are the downstream targets inducing cellular growth. By using protein-based as well as pharmacological inhibitors and the shRNA technique, we demonstrate that in neonatal rat cardiomyocytes (NRCM) Rac1 is activated via a cascade involving the α(1A)-AR subtype, G(i)βγ, the phosphoinositide-3'-kinase and the guanine nucleotide exchange factor Tiam1. We further demonstrate that this signaling induces an increase in protein synthesis, cell size and atrial natriuretic peptide expression. We identified the p21-activated kinase 2 (PAK2) as a downstream effector of Rac1 and were able to link this cascade to the activation of the pro-hypertrophic kinases ERK1/2 and p90RSK. Our data thus reveal a prominent role of the α(1A)-AR/G(i)βγ/Tiam1-mediated activation of Rac1 and its effector PAK2 in the induction of hypertrophy in NRCM.

Cardioprotective Effect of Beta-3 Adrenergic Receptor Agonism: Role of Neuronal Nitric Oxide Synthase

The aim of this study was to determine whether activation of β3-adrenergic receptor (AR) and downstream signaling of nitric oxide synthase (NOS) isoforms protects the heart from failure and hypertrophy induced by pressure overload.β3-AR and its downstream signaling pathways are recognized as novel modulators of heart function. Unlike β1- and β2-ARs, β3-ARs are stimulated at high catecholamine concentrations and induce negative inotropic effects, serving as a "brake" to protect the heart from catecholamine overstimulation.C57BL/6J and neuronal NOS (nNOS) knockout mice were assigned to receive transverse aortic constriction (TAC), BRL37344 (β3 agonist, BRL 0.1 mg/kg/h), or both.Three weeks of BRL treatment in wild-type mice attenuated left ventricular dilation and systolic dysfunction, and partially reduced cardiac hypertrophy induced by TAC. This effect was associated with increased nitric oxide production and superoxide suppression. TAC decreased endothelial NOS (eNOS) dimerization, indicating eNOS uncoupling, which was not reversed by BRL treatment. However, nNOS protein expression was up-regulated 2-fold by BRL, and the suppressive effect of BRL on superoxide generation was abrogated by acute nNOS inhibition. Furthermore, BRL cardioprotective effects were actually detrimental in nNOS(-/-) mice.These results are the first to show in vivo cardioprotective effects of β3-AR-specific agonism in pressure overload hypertrophy and heart failure, and support nNOS as the primary downstream NOS isoform in maintaining NO and reactive oxygen species balance in the failing heart.

Reduced Vascular Smooth Muscle (VSM) Sensitivity to Contraction in ex vivo Hemorrhaged Rabbit Epigastric Artery (EA)

Compensation to hemorrhage includes vasoconstrictor‐induced VSM contraction. Severe hemorrhage can lead to reduced VSM reactivity to vasoconstrictors and decompensation. Vasoconstrictors not only cause VSM contraction, but also can activate a cellular negative feedback mechanism that causes prolonged VSM desensitization, termed VSM memory. To explore the hypothesis that VSM memory plays a role in decompensation, we studied EA reactivity ex vivo 45 min after severe hemorrhage. Compared to control rabbit EA removed before hemorrhage, EA after hemorrhage displayed depressed contractions to phenylephrine (PE) and histamine (HA). These data suggest that VSM memory participates in vascular decompensation during hemorrhagic shock. We more fully characterized VSM memory in rabbit and mouse arteries in vitro. Strong receptor stimulation (10–30 μM PE) for 30 min followed by PE washout to cause complete relaxation reduced the ability of G protein‐coupled receptor (GPCR) agonists (PE, HA, U‐46619 and vasopressin) and a non‐GPCR agonist (KCl) to subsequently contract renal, femoral, epigastric and mesenteric arteries for at least 1 hr after PE washout. These data indicate that high catecholamine concentrations can induce a generalized VSM desensitization in rabbit and mouse arteries (VSM memory) that may be responsible, in part, for vascular decompensation during hemorrhage. Funding: R01HL061320

Early adrenaline administration does not improve circulatory recovery during resuscitation from severe asphyxia in newborn piglets

Aim of the studyTo investigate the effects of early intravenous adrenaline administration on circulatory recovery, cerebral reoxygenation, and plasma catecholamine concentrations, after severe asphyxia-induced bradycardia and hypotension. MethodsOne-day-old piglets were left in apnoea until heart rate and mean arterial pressure were less than 50min−1 and 25mmHg, respectively. They randomly received adrenaline, 10μgkg−1 (n=16) or placebo (n=15) and were resuscitated with air ventilation and, when needed, closed-chest cardiac massage (CCCM). Eight not asphyxiated animals served as time controls. ResultsCCCM was required in 13 piglets given adrenaline and in 13 given placebo. Time to return of spontaneous circulation was: 72 (66–85)s vs. 77 (64–178)s [median (quartile range)] (p=0.35). Time until cerebral regional oxygen saturation (CrSO2) had increased to 30% was 86 (79–152)s vs. 126 (88–309)s (p=0.30). The two groups did not differ significantly in CrSO2, heart rate, arterial pressure, right common carotid artery blood flow, or number of survivors: 13 vs. 11 animals. Plasma concentration of adrenaline, 2.5min after resuming ventilation, was 498 (268–868)nmoll−1vs. 114 (80–306)nmoll−1 (p=0.01). Corresponding noradrenaline concentrations were 1799 (1058–4182)nmoll−1vs. 1385 (696–3118)nmoll−1 (ns). In the time controls, the concentrations were 0.4 (0.2–0.6)nmoll−1 of adrenaline and 1.8 (1.3–2.4)nmoll−1 of noradrenaline. ConclusionThe high endogenous catecholamine levels, especially those of noradrenaline, may explain why early administered adrenaline did not significantly improve resuscitation outcome.

Cardiac dysfunction in cirrhosis – does adrenal function play a role? A hypothesis

Cirrhotic cardiomyopathy (CCM), a condition of unknown pathogenesis, is characterized by suboptimal ventricular contractile response to stress, diastolic dysfunction and QT interval prolongation. It is most often found in patients with advanced cirrhosis. It is clinically relevant during stressful conditions, such as sepsis, bleeding and surgery. CCM reverses after liver transplantation and potentially has a role in the pathogenesis of hepatorenal syndrome. In adrenal insufficiency (AI), cardiac dysfunction is a feature with low ejection fraction, decreased left ventricular chamber size and electrocardiographic abnormalities, including QT interval prolongation. With optimal diagnostic tests, AI is present in approximately 10% of patients with cirrhosis, particularly in those with advanced disease. Down-regulation and decreased number of beta-adrenergic receptors, and high catecholamine levels are common to both cardiac conditions. Thus, AI may play a role in CCM. Steroid replacement therapy reverses cardiac changes in AI, and may do so for CCM, with important therapeutic implications; this needs formal evaluation.

褐色細胞腫に対する腹腔鏡下手術の臨床的検討―手術時間と術中高血圧に影響する術前の臨床パラメーターの解析―

We retrospectively analyzed the preoperative clinical parameters which influence operative time and intraoperative maximum systolic blood pressure in patients undergoing laparoscopic adrenalectomy for pheochromocytoma. Between January 1992 and September 2010, we performed 28 laparoscopic adrenalectomies for pheochromocytoma at Hamamatsu University School of Medicine. These 28 cases were characterized based on the following parameters: body mass index (BMI), tumor size, history of hypertension, preoperative blood pressure, serum concentration of catecholamine, and 24-h urinary excretion of catecholamine metabolite. We retrospectively analyzed whether or not these parameters influenced operative time or intraoperative maximum systolic blood pressure. All 28 cases of laparoscopic adrenalectomy were performed safely and without intraoperative complications and needed neither blood transfusion nor conversion to laparotomy. The median operative time was 203 minutes, and intraoperative hypertension (systolic blood pressure > 200 mmHg) occurred in 46% (13/28) of cases. Median day of discharge in all patients was post-operative day 5. Significant positive correlation was shown between tumor size and operative time and between intraoperative maximum systolic blood pressure and serum concentration of catecholamine or 24-h urinary excretion of catecholamine metabolite (p < 0.05). The lengthened operative time for large tumors and elevated intraoperative blood pressure for tumors with high preoperative catecholamine activity necessitate careful perioperative management in patients receiving laparoscopic adrenalectomy for pheochromocytoma.

Hormonal modulation of the heat shock response: insights from fish with divergent cortisol stress responses

Acute temperature stress in animals results in increases in heat shock proteins (HSPs) and stress hormones. There is evidence that stress hormones influence the magnitude of the heat shock response; however, their role is equivocal. To determine whether and how stress hormones may affect the heat shock response, we capitalized on two lines of rainbow trout specifically bred for their high (HR) and low (LR) cortisol response to stress. We predicted that LR fish, with a low cortisol but high catecholamine response to stress, would induce higher levels of HSPs after acute heat stress than HR trout. We found that HR fish have significantly higher increases in both catecholamines and cortisol compared with LR fish, and LR fish had no appreciable stress hormone response to heat shock. This unexpected finding prevented further interpretation of the hormonal modulation of the heat shock response but provided insight into stress-coping styles and environmental stress. HR fish also had a significantly greater and faster heat shock response and less oxidative protein damage than LR fish. Despite these clear differences in the physiological and cellular responses to heat shock, there were no differences in the thermal tolerance of HR and LR fish. Our results support the hypothesis that responsiveness to environmental change underpins the physiological differences in stress-coping styles. Here, we demonstrate that the heat shock response is a distinguishing feature of the HR and LR lines and suggest that it may have been coselected with the hormonal responses to stress.

Successful bridge to recovery using a microaxial blood pump in a patient with electrical storm and cardiogenic shock

A 59-year-old patient with dilated cardiomyopathy and incessant ventricular tachycardia leading to progressive cardiogenic shock is presented. Due to hemodynamic instability, high dose catecholamines were required in addition to the implantation of an intraaortic balloon pump (IABP), which, however, appeared to further augment the frequency and duration of ventricular tachycardias. The implantation of a microaxial blood pump allowed catecholamine administration to be terminated, thereby, ending this vicious circle of catecholamine-driven electrical storm. Within 5days, the patient was hemodynamically stabilized and kidney and liver function recovered with the support of intensive antiarrhythmic therapy (amiodarone, mexiletine, sotalol). During a 24-month follow-up, the patient had no further ICD shocks and no rehospitalization was required for treatment of congestive heart failure.

Intravenous Arginine Vasopressin Infusion in Refractory Vasodilatory Shock: A Clinical Study

To assess the efficacy of arginine vasopressin (AVP) as a rescue therapy in children with catecholamine refractory vasodilatory shock and its effect on various hemodynamic, clinical, and laboratory variables. This prospective hospital based study was conducted from January 2008 through July 2008 at a tertiary pediatric cardiac critical care unit. Twelve post cardiac surgery patients with advanced vasodilatory shock requiring intravenous vasopressin infusion longer than 60 min were included and continuous vasopressin infusion was given. The primary outcome measures were restoration of Mean arterial blood pressure (MAP) after starting AVP infusion and decrease in other concurrent catecholamines requirement. The secondary outcome measures were survival to hospital discharge, adverse effects, and laboratory variables. Vasopressin was infused in the dose range of 0.0005 to 0.003 units/kg/min for a mean duration of 55.6 h. MAP improved from 41.08 ± 6.15 mmHg at baseline to 48.92 ± 10.05 mmHg after 1 h (P < 0.05), to 57.01 ± 8.30 mmHg after 4 h of AVP infusion (P < 0.001), and to 62.33 ± 8.55 mmHg after 12 h (P < 0.001), which further increased to 71.75 ± 9.55 mmHg after 24 h (P < 0.001). Inotrope score and requirement of other concurrent inotropes declined significantly in all patients after starting AVP infusion (P < 0.001). Lactate levels also declined significantly (P < 0.0001). No significant adverse effect due to end organ ischemia was observed. Only one patient expired while on vasopressin infusion due to refractory hypotension. Concurrent addition of vasopressin at an appropriate stage help improving MAP significantly with decreased dependence on high dose catecholamines without any significant adverse effects.

A High Admission Syndecan-1 Level, A Marker of Endothelial Glycocalyx Degradation, Is Associated With Inflammation, Protein C Depletion, Fibrinolysis, and Increased Mortality in Trauma Patients

To investigate the association between markers of acute endothelial glycocalyx degradation, inflammation, coagulopathy, and mortality after trauma. Hyperinflammation and acute coagulopathy of trauma predict increased mortality. High catecholamine levels can directly damage the endothelium and may be associated with enhanced endothelial glycocalyx degradation, evidenced by high circulating syndecan-1. Prospective cohort study of trauma patients admitted to a Level 1 Trauma Centre in 2003 to 2005. Seventy-five patients were selected blindly post hoc from 3 predefined injury severity score (ISS) groups (<16, 16-27, >27). In all patients, we measured 17 markers of glycocalyx degradation, inflammation, tissue and endothelial damage, natural anticoagulation, and fibrinolysis (syndecan-1, IL-6, IL-10, histone-complexed DNA fragments, high-mobility group box 1 (HMGB1), thrombomodulin, von Willebrand factor, intercellular adhesion molecule-1, E-selectin, protein C, tissue factor pathway inhibitor (TFPI), antithrombin, D-dimer, tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), soluble uPA receptor, and plasminogen activator inhibitor-1), hematology, coagulation, catecholamines, and assessed 30-day mortality. Variables were compared in patients stratified according to syndecan-1 median. Patients with high circulating syndecan-1 had higher catecholamines, IL-6, IL-10, histone-complexed DNA fragments, HMGB1, thrombomodulin, D-dimer, tPA, uPA (all P < 0.05), and 3-fold increased mortality (42% vs. 14%, P = 0.006) despite comparable ISS (P = 0.351). Only in patients with high glycocalyx degradation was higher ISS correlated with higher adrenaline, IL-6, histone-complexed DNA fragments, HMGB1, thrombomodulin, and APTT, lower protein C (all P < 0.05), unchanged TFPI and blunted D-dimer response (P < 0.001) because D-dimer was profoundly increased even at low ISS. After adjusting for age and ISS, syndecan-1 was an independent predictor of mortality (OR: 1.01 [95%CI, 1.00-1.02]; P = 0.043). In trauma patients, high circulating syndecan-1, a marker of endothelial glycocalyx degradation, is associated with inflammation, coagulopathy and increased mortality.

The effect of nitrous oxide on S-adenosylmethionine levels in mouse brain

Mice were exposed to nitrous oxide (50%) for up to 24 h and S-adenosylmethionine (SAMe) levels measured in corpus striatum and cerebellum, areas with high and low catecholamine turnover rates, respectively. After 4 h, levels were 21 and 8% and after 6 h, 33 and 14% lower than controls in striatum and cerebellum, respectively. Thus, the effect was more pronounced in corpus striatum, the area with the presumed higher rate of catecholamine O-methylation. With continued exposure to nitrous oxide SAMe concentrations in the two areas returned to nearly normal at 24 h. The observation that levels did not continue to decline, and even returned towards control levels, while animals were still in the presence of the gas suggests that a mechanism other than that of methionine synthase inhibition may have been responsible for the initial effect. Alternatively, some other source of SAMe may have become available to compensate for the inhibition of the enzyme.

Continuous Terlipressin Infusion as Rescue Treatment in a Case Series of Children with Refractory Septic Shock

Despite intensive therapy, refractory pediatric septic shock has a high rate of morbidity and mortality. Additional treatments are needed to improve outcomes in such cases. To report the clinical effects of continuous terlipressin infusion as rescue treatment for children with septic shock refractory to high catecholamine doses. Sixteen episodes of catecholamine-resistant septic shock were recorded in 15 children (aged from newborn to 15 years) who received compassionate rescue treatment with terlipressin at 6 pediatric intensive care units. Terlipressin treatment consisted of a loading dose (20 μg/kg) followed by continuous infusion at a rate of 4-20 μg/kg/h. Terlipressin was titrated at increases of 1 μg/kg/h to maintain mean arterial pressure (MAP) in normal range for age and to reduce catecholamine dosage. The main outcome was survival of the episode. Secondary outcomes included hemodynamic effects, ischemia, and terlipressin-related adverse events. Terlipressin increased median MAP from 48 (range 42-63) to 68 (45-115) mm Hg 30 minutes after terlipressin administration (p < 0.01). MAP was subsequently sustained, which allowed for the reduction of norepinephrine infusion from 2 μg/kg/min (1-4) at baseline to 1.5 μg/kg/min (0.4-4) at 1 hour, 1.3 μg/kg/min (0-8) at 4 hours, 1 μg/kg/min (0-2) at 12 hours, 0.45 μg/kg/min (0-1.4) at 24 hours, and 0 μg/kg/min (0-0.6) at 48 hours (p < 0.05 vs baseline in all cases). In 8 (50%) of the 16 septic shock episodes the patients survived, 7 (44%) without sequelae. One patient survived with sequelae (minor amputation and mild cutaneous ischemia). Eight patients had signs of ischemia at admission; terlipressin induced reversible ischemia in another 4 patients. Meningococcal infection, prior ischemia, and MAP were risk factors for mortality. Continuous terlipressin infusion may improve hemodynamics and survival in some children with refractory septic shock. Terlipressin could contribute to tissue ischemia.

Acute coagulopathy of trauma: Balancing progressive catecholamine induced endothelial activation and damage by fluid phase anticoagulation

Acute coagulopathy of trauma predicts a poor clinical outcome. Tissue trauma activates the sympathoadrenal system resulting in high circulating levels of catecholamines that influence hemostasis dose-dependently through immediate effects on the two major compartments of hemostasis, i.e., the circulating blood and the vascular endothelium. There appears to be a dose-dependency with regards to injury severity and the hemostatic response to trauma evaluated in whole blood by viscoelastic assays like thrombelastography (TEG), changing from normal to hypercoagulable, to hypocoagulable and finally hyperfibrinolytic in severely injured patients. Since high catecholamine levels may directly damage the endothelium and thereby promote systemic coagulation activation, we hypothesize that the progressive hypocoagulability and ultimate hyperfibrinolysis observed in whole blood with increasing injury severity, is an evolutionary developed response that counterbalances the injury and catecholamine induced endothelial activation and damage. Given this, the rise in circulating catecholamines in trauma patients may favor a switch from hyper- to hypocoagulability in the blood to keep the progressively more procoagulant microvasculature open. The hypothesis delineated in the present paper thus infers that the state of the fluid phase, including its cellular elements, is a consequence of the degree of the tissue injury and importantly, critically related to the degree of endothelial damage, with a progressively more procoagulant endothelium inducing a gradient of increasing anticoagulation towards the fluid phase. The implications of this hypothesis may include targeted treatment strategies according to the degree of sympathoadrenal response as evaluated by whole blood viscoelastical hemostatic assays in trauma patients.

Fat as a fuel: emerging understanding of the adipose tissue–skeletal muscle axis

The early pioneers in the field of metabolism during exercise such as Lindhard and Krogh understood the importance of fat as a fuel for muscle contraction. But they could not have understood the details of the pathways involved, as neither the metabolic role of adipose tissue nor the transport role of non-esterified fatty acids (NEFA) in the plasma was clearly understood at the time. We now recognize that the onset of muscular contraction coincides with an increase in the delivery of NEFA from adipose tissue, probably coordinated by the sympatho-adrenal system. During light exercise, adipose tissue-derived NEFA make up the majority of the oxidative fuel used by muscle. As exercise is prolonged, the importance of NEFA increases. The onset of exercise is marked by an increased proportion of NEFAs entering beta-oxidation rather than re-esterification and recycling. At moderate intensities of exercise, other sources of fat, potentially plasma- and intramyocellular-triacylglycerol, supplement the supply of plasma NEFA. The delivery of NEFA is augmented by increased adipose tissue blood flow and by other stimuli such as atrial natriuretic peptide. Only during high-intensity exercise is there a failure of adipose tissue to deliver sufficient fatty acids for muscle (which is coupled with an inability of muscle to use them, even when fatty acids are supplied artificially). This limitation of adipose tissue NEFA delivery may reflect some feedback inhibition of lipolysis, perhaps via lactate, or possibly alpha-adrenergic inhibition of lipolysis at very high catecholamine concentrations.

Is stress cardiomyopathy the underlying cause of ventricular dysfunction associated with brain death?

Most deaths in the first 30 days after cardiac transplantation are due to failure of the donor heart, often with the clinical picture of right ventricular failure. Indeed, there is a significant reduction in contractility of the human donor heart and loss of contractile reserve before and soon after transplantation. This myocardial insult appears in association with brain death in the donor and follows a "catecholamine storm" associated with a rapidly rising intracranial pressure. Microscopy of the myocardium in organ donors shows a picture typical of catecholamine-induced injury and similar to changes found in endomyocardial specimens of stress cardiomyopathy (catecholamine-induced cardiomyopathy, or Takotsubo cardiomyopathy). There are 3 common features between stress cardiomyopathy and the heart of a brain-dead donor: exposure of the heart to unusually high catecholamine levels, ventricular dysfunction, and prompt recovery. Stress cardiomyopathy is a temporary myocardial dysfunction that has been described after sub-arachnoid hemorrhage, traumatic head injury, pheochromocytoma, acute emotional distress, exogenous administration of catecholamines, and non-related surgery. Given the common features of this catecholamine-mediated myocardial insult, we ask if brain-dead donor heart dysfunction is an extreme variant of stress cardiomyopathy? And, if so is it, like stress cardiomyopathy, reversible? Can we therefore expect recovery of the dysfunctional donor heart over time, thereby permitting increased use of hearts offered for transplantation?