Exogenous Catecholamines Research Articles

TRANSIENT PERFUSION DEFECTS IN TAKOTSUBO CARDIOMYOPATHY

PURPOSE: Transient left ventricular apical ballooning syndrome or takotsubo cardiomyopathy (TC) is characterized by symptoms and electrocardiographic changes similar to acute myocardial infarction, in presences of non-obstructive coronaries. We describe six patients with LVABS to illustrate the clinical features and a possible cause of this transient left ventricular systolic dysfunction. These patients developed TC on exposure to exogenous catecholamines.

Stress-Related Cardiomyopathy Syndromes

The relationship between the heart and the brain is complex and integral in the maintenance of normal cardiovascular function. Certain pathological conditions can interfere with the normal brain-heart regulatory mechanisms and result in impaired cardiovascular function. The mechanisms through which the central and autonomic nervous systems regulate the heart and the manner in which their impairment adversely affects cardiovascular function have recently been reviewed by Samuels.1 The purpose of this article is to provide an up-to-date review of the clinical presentation of the stress-related cardiomyopathy syndromes, discuss possible causal mechanisms, and highlight the similarities and differences between them.2–16 The stress-related cardiomyopathies appear similar in that they seemingly occur during times of enhanced sympathetic tone and may be precipitated in part or entirely by excessive endogenous or exogenous catecholamine stimulation of the myocardium. Although significant clinical overlap exists in those presenting with stress-associated cardiomyopathy, it is unclear whether myocardial adrenergic hyperstimulation is the only pathophysiological mechanism responsible for these syndromes (Tables 1 and 2⇓). View this table: Table 1. Precipitants of Stress Cardiomyopathy View this table: Table 2. Morphological LV Variants of Stress Cardiomyopathy In the early 1990s, Japanese authors began reporting a unique, reversible cardiomyopathy that appeared to be precipitated by acute emotional stress.2,13,16 They found that these patients were usually postmenopausal women and often developed signs and symptoms of an acute coronary syndrome (ACS) proximate to a strong emotional stressor associated with a transient apical and midventricular wall motion abnormality despite the lack of obstructive coronary artery disease (CAD) at the time of emergent coronary angiography. This syndrome was initially given the name Takotsubo cardiomyopathy (TC) and has subsequently been referred to as the apical ballooning syndrome and broken heart syndrome. It is now recognized that TC can also occur in the setting of acute medical illness and after surgery. TC …

Catecholamines induce an inflammatory response in human hepatocytes

The liver is an early target organ in sepsis, severe sepsis, and septic shock, contributing to multiple organ failure, and both lipopolysaccharide and gut-derived catecholamines are implicated in the occurrence of hepatocellular dysfunction. Treatment of septic shock involves administration of vasoactive agents such as exogenous catecholamines or vasopressin in order to reestablish blood pressure. As a prelude to clinical application, we tested the hypothesis that catecholamines could modulate the lipopolysaccharide-induced inflammatory response and function in human liver. An in vitro human cell culture study. Research laboratory of an academic institution. Primary human hepatocytes and human hepatoma HepaRG cells. Primary human hepatocytes and human hepatoma HepaRG cells were exposed to lipopolysaccharide to evaluate effects of epinephrine and several other compounds (norepinephrine, dobutamine, dopamine, dopexamine, phenylephrine, clonidine, salbutamol, and vasopressin). Markers of inflammation (interleukin-6, C-reactive protein) and drug metabolism (cytochrome P450 [CYP] 3A4, CYP2B6, CYP1A2, CYP2E1, constitutive androstane receptor, pregnane X receptor) were analyzed. Transcripts of C-reactive protein and CYP3A4 were strongly increased and depressed respectively after a 24-hr treatment with 10 ng/mL lipopolysaccharide. Co-treatment with either of the catecholamines failed to reverse lipopolysaccharide effects, whereas when added alone, epinephrine, and to a lesser extent norepinephrine, salbutamol, and dobutamine, mimicked lipopolysaccharide effects. Suppression of CYP3A4 implicated beta-adrenergic receptors and was mediated through overproduction of interleukin-6. By contrast, vasopressin did not elicit an inflammatory response or modify CYP3A4 expression. Some catecholamines can induce an inflammatory response and exacerbate the hepatic dysfunction observed during sepsis, favoring the idea that catecholamines could alter the biotransformation of drugs metabolized by CYP3A4 and that alternative vasoactive agents, such as vasopressin, merit further investigation in septic shock patients.

Coronary vasospasm during anesthesia induction: awareness, recognition, possible mechanisms, anesthetic factors, and treatment

We describe a patient who developed severe ST-segment elevation, pulseless ventricular tachycardia, and cardiac arrest during induction of general anesthesia. This transient ST-segment elevation may have been the result of coronary artery spasm. Awareness of this variant of coronary artery vasospasm—Prinzmetal angina—in patients without clear symptoms or established ischemic heart disease, is the key to successful outcome. Recommended preparations and treatments are preoperative calcium channel blockers, nitroglycerin available intraoperatively, reduction of endogenous or exogenous catecholamines, and vigilant monitoring.

Cardiovascular and metabolic responses to catecholamine and sepsis prognosis: a ubiquitous phenomenon?

Many parameters have been associated with sepsis prognosis. In the present issue of Critical Care, Kumar and colleagues demonstrate that a preserved cardiac answer to dobutamine evaluated by radionucleotide measurements was associated with a better prognosis during septic shock. In this context, it is interesting to note that not only is the cardiac response to catecholamine stimulation associated with prognosis, but also the vascular and metabolic responses are associated. The ability of exogenous catecholamine to increase the arterial pressure (dopamine test) or to increase the lactate level is also related to prognosis. According to the ubiquitous character of catecholamine sensitivity, therefore, we should think in terms of cellular ability to respond to catecholamines in defining the concept of physiological reserve.

Effect of exogenous catecholamines on tumor necrosis factor alpha, interleukin-6, interleukin-10 and beta-endorphin levels following severe trauma

Cytokines and endogenous opioids are mediators of the post traumatic inflammatory response. The aim of this study was to determine the effect of exogenous catecholamines on Tumor Necrosis Factor alpha (TNFa), interleukin-6 (IL-6), interleukin-10 (IL-10) and Beta(β)-endorphin levels in patients with severe trauma, during the first 24 h after injury. Forty four traumatized patients with haemorrhage class III and IV were included in the study. Patients were divided in two groups: Group 1 (adrenergic, n = 22) and Group 2 (non adrenergic, n = 22), depending on the use of exogenous catecholamines. Blood samples were collected at 0, 2, 4 and 24 h time points. Baseline values were different between the two groups, but an altered pattern of release was observed for TNFa, IL-6, IL-10 and β-endorphin levels in patients treated with catecholamines. ICU stay was longer for the adrenergic group, while survival after 1 month was significantly lower. Findings support an altered pattern of cytokine release during the early phase after trauma, probably due to catecholamine presence.

Effects of anaerobic exercise accompanying catch-and-release fishing on blood-oxygen affinity of the sandbar shark ( Carcharhinus plumbeus, Nardo)

Recovery from anaerobic exercise is thought to be prolonged in elasmobranchs because they lack several mechanisms for maintaining or increasing oxygen delivery that are present in teleosts. For example, teleosts increase hematocrit and maximal blood-oxygen carrying capacity through red cell ejection from the spleen. Teleosts also counteract the reduction in hemoglobin oxygen affinity resulting from metabolic acidosis through an adrenergic-mediated increase in red cell Na +–H + exchanger activity. To begin to assess the consequences of anaerobic exercise accompanying catch-and-release fishing occurring within the estuarine nursery habitats of juvenile sandbar sharks ( Carcharhinus plumbeus, Nardo), we constructed blood-oxygen equilibrium curves using samples from individuals 1 h after capture by hook and line (exercise-stressed) and samples from fully-recovered animals maintained in a shore-side tank (control sharks). We also compared exercise-stressed and control sharks for hemoglobin concentration, hematocrit, red cell count, intracellular pH, and nucleoside triphosphate concentration ([NTP]). In contrast to results from previous studies on elasmobranchs, we found an elevation in both hematocrit (≈ 21%) and blood hemoglobin concentration (≈ 10%) in exercise-stressed sharks. There was also clear evidence of red cell swelling. Mean red cell volume was ≈ 28% higher and mean cell hemoglobin concentration was ≈ 10% lower in exercise-stressed sharks. Most important, in spite of significant metabolic acidosis (0.3 pH units), blood from exercise-stressed sharks had an oxygen affinity equivalent to that of blood from control sharks. This was a direct consequence of intracellular pH being alkalinized by approximately 0.15 pH units relative to plasma pH in exercise-stressed sharks. Our results using isolated hemoglobin solutions showed that the observed reduction (≈ 15%) in intracellular [NTP] also contributed to the leftward shift in the oxygen equilibrium curves. As expected, we found sandbar shark red cells to be unresponsive to exogenous catecholamines. Regardless, sandbar sharks appear able to prevent the decrease in blood-oxygen affinity resulting from anaerobic exercise (and the concomitant decreases in plasma pH), as has been well-documented in teleosts. Our results suggest, therefore, that oxygen delivery following exhaustive exercise is not necessarily compromised in juvenile sandbar sharks, and that hook and line capture and subsequent release do not increase rates of mortality, although both are yet to be directly confirmed.

Mineralocorticoid effects due to cortisol inactivation overload explain the beneficial use of hydrocortisone in septic shock

The role of corticosteroids in septic shock remains controversial despite their use for over 50 years. Large prospective trials of their use continue with the aim of resolving the controversy. These may well remain indecisive if basic endocrine principles are ignored. Review of the available evidence suggests that use of synthetic glucocorticoids is harmful but hydrocortisone beneficial. Consideration of the basic properties of the corticosteroids used and their receptors suggest an explanation for their differing therapeutic effects. The harmful synthetic glucocorticoids have no or reduced mineralocorticoid effects in contrast with the significant mineralocorticoid effects of hydrocortisone at the doses which have been found to be beneficial. The potent synthetic mineralocorticoid fludrocortisone is well recognised to raise peripheral resistance by sensitising the resistance vessels to endogenous or exogenous catecholamines and also causes metabolic alkalosis. We provide evidence to support our hypothesis that at the doses of hydrocortisone used, cortisol inactivation overload is the basis of the beneficial effect. The consequent mineralocorticoid effects result in increased sensitivity of the resistance vessels to endogenous and exogenous catecholamines with an increase in peripheral resistance correcting shock. In addition the metabolic alkalotic component of mineralocorticoid effect would tend to correct the prevailing metabolic acidosis. Hydrocortisone also has an attenuating, as opposed to the suppressing effect of synthetic glucocorticoids on the immune response which is also regarded as beneficial.

Propofol infusion syndrome

The clinical features of propofol infusion syndrome (PRIS) are acute refractory bradycardia leading to asystole, in the presence of one or more of the following: metabolic acidosis (base deficit > 10 mmol.l(-1)), rhabdomyolysis, hyperlipidaemia, and enlarged or fatty liver. There is an association between PRIS and propofol infusions at doses higher than 4 mg.kg(-1).h(-1) for greater than 48 h duration. Sixty-one patients with PRIS have been recorded in the literature, with deaths in 20 paediatric and 18 adult patients. Seven of these patients (four paediatric and three adult patients) developed PRIS during anaesthesia. It is proposed that the syndrome may be caused by either a direct mitochondrial respiratory chain inhibition or impaired mitochondrial fatty acid metabolism mediated by propofol. An early sign of cardiac instability associated with the syndrome is the development of right bundle branch block with convex-curved ('coved type') ST elevation in the right praecordial leads (V1 to V3) of the electrocardiogram. Predisposing factors include young age, severe critical illness of central nervous system or respiratory origin, exogenous catecholamine or glucocorticoid administration, inadequate carbohydrate intake and subclinical mitochondrial disease. Treatment options are limited. Haemodialysis or haemoperfusion with cardiorespiratory support has been the most successful treatment.

CONTINUOUSLY INFUSED GLIPIZIDE REVERSES THE HYPERDYNAMIC CIRCULATION IN OVINE ENDOTOXEMIA

In advanced sepsis, hemodynamic support is often complicated by a tachyphylaxis against exogenous catecholamines. Although activation of adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels plays a pivotal role in the pathogenesis of hyperdynamic vasodilatory shock, previous studies demonstrated only a transient increase in mean arterial pressure (MAP) after bolus administration of K(ATP) channel inhibitors. We hypothesized that a continuous infusion of the sulfonylurea glipizide, a K(ATP) channel inhibitor, may reverse cardiovascular dysfunctions in sepsis permanently. Eighteen adult sheep were instrumented for chronic study. After a baseline measurement in healthy ewes, endotoxin (Salmonella typhosa, 10 ng kg(-1) min(-1)) was continuously infused for 19 h. After 16 h of endotoxemia, the surviving sheep (n = 14) were randomly assigned to be treated with either glipizide (5 mg/kg, followed by a continuous infusion of 8 mg kg(-1) h(-1)) or placebo (normal saline; each n = 7). Measurements of cardiopulmonary hemodynamics, global oxygen transport, acid-base status, and urine output were performed in the healthy state, after 16 h of endotoxemia, and during 3 h of glipizide infusion. Continuous infusion of glipizide reversed the endotoxin-induced hyperdynamic circulation, as indicated by significant increases in MAP and systemic vascular resistance index, as well as decreases in cardiac index and heart rate (P < 0.001 each). In addition, glipizide increased urine output as compared with untreated controls (P < 0.001). The anticipated decrease in glucose plasma levels was prevented by infusion of glucose 5%. From these results, we conclude that continuous glipizide infusion may represent a useful therapeutic option in the treatment of arterial hypotension related to sepsis and systemic inflammatory response syndrome.

Reply

EDITOR: We thank Dr McCahon and colleagues for their interest in our study [1]. Dr McCahon enquires whether the effect of ephedrine on bispectral index scores (BIS) values were clinically significant or not. In this study, we examined whether ephedrine increased BIS values during propofol anaesthesia as it does during sevoflurane anaesthesia [2] and whether ephedrine decreased propofol concentrations. Johnson and colleagues [3] reported arousal following isoprenaline administration during propofol anaesthesia. They also examined the effect of intravenous epinephrine on BIS and sedation, reporting that mean BIS values increased from 63 to 76 and exogenous catecholamines seemed to display an arousal effect [4]. This could be due to changes in neurotransmitter levels in the brain. The adrenergic system has a role to play in the process of arousal from anaesthesia, and this has been previously demonstrated [5]. β-receptors in the reticular-activating system interact with the information processing in the thalamus. However, another possible explanation that propofol concentration decreased due to increased cardiac output on administration of a catecholamine had not been examined. In our previous study, we showed decreases in propofol concentration with increased cardiac output following dopamine administration [6]. Ephedrine exerts a potent stimulating effect on the central nervous system [7]. Ishiyama and colleagues [2] reported that ephedrine increased BIS during sevoflurane anaesthesia. We examined the effect of ephedrine on propofol concentrations and on BIS. Our study showed that ephedrine increased BIS to >60 in eight of 20 patients without changing the propofol concentrations. In our study, post-operative interviews revealed that there were no patients who had any recall during the surgical procedure. No other study reports arousal following ephedrine administration. As suggested by McCahon and colleagues, the clinical significance in the effect of ephedrine on BIS is not clear from our study. Further work on anaesthetic depth is required concerning the clinical significance of the effect of drugs that act on the central nervous system.

Levosimendan: The Inotrope of Choice in Cardiogenic Shock Secondary to Takotsubo Cardiomyopathy?

Takotsubo cardiomyopathy (TC) has become an increasingly recognised entity in Western literature since its initial reporting in Japan. The pathogenesis underlying the myocardial stunning and systolic dysfunction is thought to be induced by elevated systemic levels of catecholamines and neuropeptides. Whilst the majority of patients are haemodynamically stable, a small proportion can develop cardiogenic shock. This creates a therapeutic dilemma because inotropic support using exogenous catecholamines (adrenaline, dobutamine, dopamine) may be counter-productive. Two cases where the calcium sensitiser levosimendan (a non-catecholamine inotrope) was used successfully in TC-related cardiogenic shock are presented. The management of circulatory compromise in TC is then discussed.

A reply

We thank Dr Dawson for his interest in using lipid emulsion as an antidote to overwhelming intoxication by local anaesthetics. We also appreciate the apparent logic of his suggestion that adrenaline given in the course of resuscitation could offset the cardiovascular effects of propofol and that therefore propofol-lipid preparations could be given instead of lipid alone. In the future, research might support or undermine his suggestion. In the meantime, we have four reasons to caution against Dr Dawson's suggestion of giving large doses of propofol to patients with inadequate cardiac output. Firstly, propofol is a potent vasodilator, as Dr Dawson concedes; it is also a potent cardiac depressant. Secondly, experience suggests patients in cardiac arrest do not in fact exhibit vasoconstriction that might usefully be reversed with propofol: on the contrary, they are vasoplegic and without cardiac output despite endogenous and exogenous catecholamines. Thirdly, different propofol preparations are now available which differ in their carrier vehicle. Diprivan® (AstraZeneca, Cheshire, UK) is supplied in an emulsion which is essentially Intralipid®, whereas Propofol-Lipuro® (B Braun, Melsungen, Germany) is supplied in Lipofundin MCT® (B Braun), which has a substantially different composition. Yet all the reported experiments and case reports of using lipid emulsion to resuscitate after intoxication with local anaesthetic have involved Intralipid®. Lastly, the treatment protocol currently proposed on http://www.lipidrescue.org suggests a 70-kg adult in cardiac arrest might receive closer to 500 ml than 100 ml of 20% lipid during resuscitation. As propofol preparations typically contain 100 mg.ml−1 of lipid, a 70-kg adult suffering circulatory collapse would need to receive an entire litre of propofol before getting the same dose of lipid. Propofol-lipid mixtures are widely and immediately available to anaesthetists in much of the world; however, we would counsel very strongly against using them in place of simple lipid emulsion in this scenario. Instead, it makes better sense, we believe, to make lipid immediately available to patients at risk. This practice may be refined or even reversed by evidence in the future. But in the meantime, it may save patients' lives, and spare them double intoxication.

SHORT-TERM EFFECTS OF GLIPIZIDE (AN ADENOSINE TRIPHOSPHATE-SENSITIVE POTASSIUM CHANNEL INHIBITOR) ON CARDIOPULMONARY HEMODYNAMICS AND GLOBAL OXYGEN TRANSPORT IN HEALTHY AND ENDOTOXEMIC SHEEP

In severe sepsis and septic shock, hemodynamic support is often complicated by a tachyphylaxis against exogenous catecholamines. Because activation of adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels plays a pivotal role in the pathogenesis of hyperdynamic vasodilatory shock, we hypothesized that it may be beneficial to administer a specific K(ATP) channel inhibitor to prevent, or at least attenuate, hemodynamic dysfunction in sepsis. The present study was designed as a prospective and controlled laboratory experiment to elucidate the short-term effects of glipizide, a specific K(ATP) channel inhibitor, on cardiopulmonary hemodynamics and global oxygen transport in healthy sheep and sheep with endotoxemia. Ten adult ewes were anesthetized and operatively instrumented with a pulmonary artery, a femoral artery, and a foley catheter. After 24 h of recovery, healthy sheep received glipizide as a bolus infusion (4 mg/kg over 15 min). After 24 h of recovery, a continuous infusion of endotoxin (Salmonella typhosa, 10 ng.kg.(-1)min) was started in the same sheep and administered for the next 17 h. After 16 h of endotoxemia, glipizide was given as described above. Administration of glipizide was followed by a transient, but significant, increase in mean arterial pressure in both healthy controls (95 +/- 3 mmHg vs. 101 +/- 2 mmHg, P < 0.05) and sheep with endotoxemia (86 +/- 3 mmHg vs. 93 +/- 3 mmHg, P < 0.05). However, the increase in mean arterial pressure was longer lasting in ewes with endotoxemia. Cardiac index, oxygen delivery index, arterial lactate concentrations, and arterial pH were not significantly affected by glipizide. Therefore, administration of glipizide may represent a beneficial therapeutic option to treat arterial hypotension resulting from sepsis and systemic inflammatory response syndrome. Additional studies are required to determine the effects of continuous infusion of glipizide in the presence of systemic inflammation.

Catecholamine Toxicity in Aromatic l-Amino Acid Decarboxylase Deficiency

This report presents the case of an adult male with aromatic L-amino acid decarboxylase deficiency who developed serious cardiac rhythm disturbances during treatment with intravenous dopamine and norepinephrine for severe hypotension. Three weeks later, he spontaneously developed atrial fibrillation while not receiving exogenous catecholamines. He died suddenly after several months. We presume cardiac arrhythmia was the most likely cause of his death. Patients with aromatic L-amino acid decarboxylase deficiency may be prone to cardiac arrhythmias at rest and also may be exceptionally sensitive to exogenous catecholamines. Therefore, close cardiac monitoring is indicated at baseline and during treatment with pressors.

Tumor necrosis factor-alpha (TNFα), intereleukin-6 (IL-6) and interleukin-10 (IL-10) levels after severe trauma: Correlation with infusion of exogenous catecholamines during the initial 24 hours

Tumor necrosis factor-alpha (TNFα), intereleukin-6 (IL-6) and interleukin-10 (IL-10) levels after severe trauma: Correlation with infusion of exogenous catecholamines during the initial 24 hours

Stimulation of alveolar epithelial fluid clearance in human lungs by exogenous epinephrine*

Because several experimental studies have demonstrated that cyclic adenosine monophosphate generation following beta-adrenoceptor activation can markedly stimulate alveolar fluid clearance, we determined whether the endogenous levels of catecholamines that occur in the pulmonary edema fluid and plasma of patients with acute lung injury are high enough to stimulate alveolar fluid clearance in the human lung. Observational clinical study. Academic university hospital and laboratory. Twenty-one patients with acute pulmonary edema plus ex vivo human lungs. Measurements of catecholamine levels in patient samples and controlled laboratory studies of the effects of these catecholamine levels on the rates of alveolar fluid clearance in ex vivo human lungs. The concentrations of both epinephrine and norepinephrine in the pulmonary edema fluid and plasma were approximately 10 M (range of 1-8x10 M) in hydrostatic pulmonary edema (n=6) and acute lung injury patients (n=15). We therefore tested whether 10 M epinephrine or norepinephrine stimulated alveolar fluid clearance in isolated human lungs and found that these epinephrine or norepinephrine concentrations did not stimulate alveolar fluid clearance. However, higher concentrations of epinephrine (10 M), but not norepinephrine (10 M), significantly stimulated alveolar fluid clearance by 84% above control. Glibenclamide (10 M) and CFTRinh-172 (10 M), cystic fibrosis transmembrane conductance regulator inhibitors, completely inhibited the epinephrine-induced stimulation of alveolar fluid clearance. These results indicate that endogenous catecholamine concentrations in pulmonary edema fluid are probably not sufficient to stimulate alveolar fluid clearance. In contrast, administration of exogenous catecholamines into the distal airspaces can stimulate alveolar fluid clearance in the human lung, an effect that is mediated in part by cystic fibrosis transmembrane conductance regulator. Therefore, exogenous cyclic adenosine monophosphate-dependent stimulation will probably be required to accelerate the resolution of alveolar edema in the lungs of patients with pulmonary edema.

Comment on "Survival Pattern in Patients with Acute Organophosphate Poisoning Receiving Intensive Care"

To the Editor: Munidasa et al. observed that refractory hypotension was strongly associated with a high early mortality from organophosphate poisoning despite adequate respiratory support, inotropes, and intensive care (1). The authors speculated that the most likely mechanism was globally impaired myocardial function as these patients typically also had pulmonary oedema. However other smaller series of similar patients with invasive monitoring suggest other mechanisms may be important. We and others have found extremely low vascular resistance in OP poisoned patients with hypotension refractory to catecholamines (2 – 4). Despite the patients being clinically atropinised the low vascular resistence responded partially to very high doses of atropine but not to other vasopressors. We postulated that this vasodilation was due to stimulation of the vascular endothelial muscarinic receptor resulting in the release of nitric oxide (2). We have observed this repeatedly in subsequent patients, and the hypotension in most patients is usually associated with a high rather than a low cardiac output (similar to septic shock) (2 – 4). There are a number of other mechanisms that may contribute to hypotension in organophosphate poisoning. Despite causing generalized vasodilation, acetylcholine can also induce vasoconstriction at sites where the endothelium is damaged (5), and this might lead to myocardial ischemia. Cardiac oxygen demand may be higher, due to the high cardiac output state and excessive endogenous or exogenous catecholamines. As well as contributing to focal ischemia, this could lead to diffuse myocardial necrosis similar to that seen with phaeochromocytoma (6,7). In addition there may be diffuse endothelial injury or cardiotoxicity from reactive oxygen species (8) or cardiac effects may be secondary to acidosis or electrolyte abnormalities (9), and others have speculated that the hypotension may be centrally mediated (3), although generally central cholinesterase inhibition leads to a pressor response (10). We agree with Munidasa et al.’s implication that refractory hypotension is the leading cause of death in anticholinesterase poisonings that are receiving maximal supportive care. It is plausible that one, many or all of these different mechanisms are important. A rational approach to the management of patients with refractory hypotension depends on the development of a much better understanding of the pathophysiology. Only then will it be clearer what treatment options are appropriate, what investigations are required, and whether treatment needs to be individualized or if clinical trials of antidotes for the hypotension are feasible.

Regulation of cardiac contractility by Rab4-modulated beta2-adrenergic receptor recycling.

Catecholaminergic activation of myocardial beta-adrenergic receptors (betaAR) is the principle mechanism regulating cardiac function. Agonists desensitize betaAR through G protein-coupled receptor kinase-mediated uncoupling and beta-arrestin-mediated internalization. Although inhibition of myocardial G protein-coupled receptor kinase-2 enhances cardiac function and reverses heart failure, pathophysiological effects of modulated betaAR internalization/recycling are unknown. We used mutation and transgenic expression of Rab4, which regulates vesicular transport of heptahelical receptors to plasma membranes, to interrogate in vivo betaAR trafficking and cardiac function. Expression of constitutively active Rab4 Q72L had no effects on cardiac structure or function, but dominant inhibitor Rab4 S27N impaired responsiveness to endogenous and exogenous catecholamines. To relate betaAR trafficking to diminished cardiac function, Rab4 mutant mice were crossbred with mice overexpressing human beta2AR. In unstimulated beta2AR overexpressors, beta2AR localized to heavier endosomes and translocated to lighter, caveolin-rich fractions after isoproterenol stimulation. Coexpression of beta2AR with activated Rab4 Q72L caused loss of receptors from heavier endosomes while retaining normal inotropy. In contrast, coexpression of beta2AR with inhibitory Rab4 S27N mimicked isoproterenol-induced receptor redistribution to caveolae, with diminished cardiac inotropy. Rab4 inhibition alone prevented resensitization after isoproterenol-induced in vivo adrenergic desensitization. Confocal and ultrastructural analyses revealed bizarre vesicular structures and abnormal accumulation of beta2AR in the sarcoplasm and subsarcollema of Rab4 S27N, but not Q72L, mice. These data provide evidence for constant bidirectional sarcollemal-vesicular betaAR trafficking in the in vivo heart and show that Rab4-mediated recycling of internalized betaAR is necessary for normal cardiac catecholamine responsiveness and resensitization after agonist exposure.

Does donor catecholamine administration affect early lung function post-transplantation?

Cadaveric lung donors have a catecholamine storm of brain death, followed by proinflammatory cytokine response and subsequent pituitary failure. After the storm, a drop in circulating catecholamines and vasoparesis occur, and exogenous catecholamines are often administered to support systemic vascular resistance and maintain organ perfusion before retrieval. The exogenous administration of catecholamines (EAC) to organ donors appears to improve outcome after renal and possibly liver transplantation, but in heart transplantation EAC is associated with a worse prognosis. EAC has been shown to increase alveolar fluid clearance after brainstem death, but the impact on graft function and recipient outcome after lung transplantation is not known. We hypothesized that EAC might be beneficial in lung transplantation.