Catecholamines refractoriness

Del Duca D, Sheth SS, Clarke AE, Lachapelle KJ, Ergina PL. Use of methylene blue for catecholamine-refractory vasoplegia from protamine and aprotinin. Ann Thorac Surg 2009 87(2) 640-2. 

Examination of data from neonates who had xmdergone complex cardiac surgery either with (n = 17) or without (n = 17) the use of vasopressin foxmd that vasopressin treatment was associated with higher urea and creatinine levels, longer period of peritoneal dialysis, reduced platelet coxmts and delayed recovery of lactate concentration [97 ]. The authors suggest that vasopressin infusion should only be used in catecholamine-refractory shock. The potentially dangerous outcomes reported in this study should be assessed carefully in future trials. 

Enhanced automaticity occurs in hypoxia, hypokalemia, hypercarbia, excessive sympathetic nervous system stimulation, or high concentrations of catecholamines. These conditions may lead to arrhythmias. Decreased automaticity may also lead to production of arrhythmias by enhancing ectopic activity in latent pacemakers (ectopic foci) or by altering conductivity and refractoriness in conduction pathways of myocardium. 

The properties of -adrenoceptor blockers that contribute to antiarrhythmic effects are antagonism of neural/humoral P-adrenergic activity, and antagonism of catecholamine-mediated electrophysiological properties, ie, increase refractory period and decrease in the rate of diastoHc depolarization, ie, decrease automaticity and slow atrioventricular conduction (1,2). 

Vasopressin causes vasoconstrictive effects that, unlike adrenergic receptor agonists, are preserved during hypoxia and severe acidosis. It also causes vasodilation in the pulmonary, coronary, and selected renal vascular beds that may reduce pulmonary artery pressure and preserve cardiac and renal function. However, based on available evidence, vasopressin is not recommended as a replacement for norepinephrine or dopamine in patients with septic shock but may be considered in patients who are refractory to catecholamine vasopressors despite adequate fluid resuscitation. If used, the dose should not exceed 0.01 to 0.04 units/min. 

Moderate doses increase conduction velocity and decrease the A-V nodal refractory period this effect may result from the initial drug-induced catecholamine release. The net effect of bretylium on A-V transmission during chronic therapy is unknown. 

Poitou P, Bohuon C Catecholamine metabolism in the rat brain after short and long term hthium administration. J Neurochem 25 535-537, 1975 Pollack MH, Hammerness P Adjunctive yohimbine for treatment of refractory depression. Biol Psychiatry 33 220-221, 1993 Pollack MH, Rosenbaum JF Verapamil in the treatment of recurrent unipolar depression. Biol Psychiatry 22 779-782, 1987... 

Direct effects on the heart are determined largely by Bi receptors, although B2 and to a lesser extent a receptors are also involved, especially in heart failure. Beta-receptor activation results in increased calcium influx in cardiac cells. This has both electrical and mechanical consequences. Pacemaker activity—both normal (sinoatrial node) and abnormal (eg, Purkinje fibers)—is increased (positive chronotropic effect). Conduction velocity in the atrioventricular node is increased (positive dromotropic effect), and the refractory period is decreased. Intrinsic contractility is increased (positive inotropic effect), and relaxation is accelerated. As a result, the twitch response of isolated cardiac muscle is increased in tension but abbreviated in duration. In the intact heart, intraventricular pressure rises and falls more rapidly, and ejection time is decreased. These direct effects are easily demonstrated in the absence of reflexes evoked by changes in blood pressure, eg, in isolated myocardial preparations and in patients with ganglionic blockade. In the presence of normal reflex activity, the direct effects on heart rate may be dominated by a reflex response to blood pressure changes. Physiologic stimulation of the heart by catecholamines tends to increase coronary blood flow. 

Spurious hyperthyroidism occurred in a child taking thyroid hormone and imipramine for enuresis (89). The ability of thyroid hormone to increase receptor sensitivity to catecholamines has long been known, and has been used to enhance the clinical response in some refractory patients, especially women. 

Fellahi JL, Benard P, Daccache G, Mourgeon E, Gerard JL. Vasodilatory septic shock refractory to catecholamines is there a role for terlipressin Ann Fr Anesth Reanim 2003 22 631 1. 

Drugs that block beta-1 receptors on the myocardium are one of the mainstays in arrhythmia treatment. Beta blockers are effective because they decrease the excitatory effects of the sympathetic nervous system and related catecholamines (norepinephrine and epinephrine) on the heart.5,28 This effect typically decreases cardiac automaticity and prolongs the effective refractory period, thus slowing heart rate.5 Beta blockers also slow down conduction through the myocardium, and are especially useful in controlling function of the atrioventricular node.21 Hence, these drugs are most effective in treating atrial tachycardias such as atrial fibrillation.23 Some ventricular arrhythmias may also respond to treatment with beta blockers. 

Lambert G, Johansson M, Agren H, Friberg P (2000) Reduced brain norepinephrine and dopamine release in treatment-refractory depressive illness evidence in support of the catecholamine hypothesis of mood disorders. Arch Gen Psychiatry 57 787-793. 

The degree to which cardiac contractihty and heart rate are altered depends on the severity of the acidosis and the rapidity with which it develops. Modest acute hypercapnia (PaC02 of 50 to 55 mm Hg) stimulates a stress-like response, with elevated catecholamines and corticosteroid hormone levels, and can result in increased cardiac output and pulmonary artery pressure. As the severity increases, cardiac output declines and vascular resistance decreases. Refractory hypotension may be present in some patients. ... 

Nitric oxide (NO), a potent endogenous vasodilator, improved arterial oxygenation and reduced pulmonary artery pressures in patients with ARDS. However, it is also associated with hypotension, as well as being a mediator of sepsis-induced refractoriness to the vasopressor effects of catecholamines. Additional work is needed to define any role for NO and ketoconazole in the management of sepsis. 

The use of propranolol (Inderal) as an antiarrhythmic is useful in the treatment of atrial tachyarrhythmias. Its mechanism is somewhat controversial. Since propranolol is a (3-adrenergic blocking agent, it seems logical to study this feature. The drug can be shown to block the cardiac effects of catecholamines. The effective refractory period of the AV node has been shown to increase. However, some quinidinelike properties have also been observed. The suggestion has been made that the antiarrhythmic action is caused by interference with the cellular transport of Ca2+. 

The major component of the antiarrhythmic mechanism of a (3-blocker undoubtedly is the termination or prevention of those tachyarrhythmias caused by excess sympathetic tone, which may in turn be the result of increased circulating catecholamines. The control of ventricular flutter that is not effectively controlled with digitalis therapy alone can also be achieved by the addition of (3-blockers since they prolong the AV refractory period. 

Naloxone is also therefore indicated for the diagnosis of acute opiate overdosage. As naloxone antagonizes the effects of beta-endorphin, it has been used to improve circulation in refractory shock, allowing prostaglandins and catecholamine to reestablish the control of circulation. 

REFRACTORINESS TO CATECHOLAMINES Exposure of catecholamine-sensitive cells and tissues to adrenergic agonists causes a progressive diminution in their capacity to respond to such agents. This phenomenon, variously termed refractoriness, desensitization, downregula-tion, or tachyphylaxis, can limit the therapeutic efficacy and duration of action of catecholamines and other agents see Chapter 1). 

Belcher, N. G., Murdoch, R., Dalton, N., Clark, T. J. H., Ress, P. J., and Lee, T. H., 1988, Circulating concentrations of histamine, neutrophil chemotactic activity, and catecholamines during the refractory period in exercise-induced asthma, J. Allergy Clin. Immunol 81 100-110. 

In a retrospective analysis of 36 patients who received intravenous levetiracetam for refractory status epilepticus [209 ] a median dose of 3000 mg/day (range 1000-9000) was used as a loading bolus or by continuous pump infusion. Status epilepticus was terminated in 69% of patients. None had cardiac dysrhythmias or significantly reduced blood pressure, or required an increase in the dose of catecholamines. Two patients had nausea and vomiting during levetiracetam loading, leading to aspiration pneumonia in one. 

If there is dear evidence of worsening prompt hospital admission for intensive therapy is necessary. As the availability of a suitable donor heart is not predictable, hemodynamic deterioration is first treated with intravenous inotropic support. When the low-cardiac-output syndrome continues to be refractory, patients are put on a mechanical circulatory device for temporary mechanical support. This bridge to transplantation concept enables patient stabilization, withdrawal of intravenous medication (inotropic agents, catecholamines, calcium sensitizers) and rehabilitation (Antretter et al. 2002a). During chronic mechanical circulatory support a low level of exercise is possible and the patients are able to walk around, to leave hospital and sometimes they are followed up by heart failure specialists in an outpatient clinic. Nearly 25% of the most recent cohort transplanted from 1 January, 2001 to 30 June, 2003 were on some type of mechanical circulatory support (Taylor et al. 2004). 

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