Use of Dopamine in Intensive Care - Essay Example

DOPAMINE USE IN INTENSIVE CARE Geremia Zito Marinosci*, Ornella Piazza^, Marco Rossi*, Rosalba Tufano^ *Dipartimento di Anestesia e Terapia Intensiva. Centro di Formazione ad Alta Tecnologia nelle Scienze Biomediche, Università Cattolica del Sacro Cuore, Campobasso. ^Università degli Studi di Napoli Federico II Abstract Dopamine remains an essential drug in Intensive Care Units. Most critical care physicians consider dopamine as a first choice drug in the treatment of many pathological conditions associated with hemodynamic failure. Its peculiar spectrum of action resides in the dose dependent interaction to different catecholamine receptors. At low doses (0, 3-5 mcg/Kg/min) dopamine exerts its effects on D1 and D2 receptors resulting in, as the kidney is concerned, natriuresis and renal vasodilation, augmentation in renal blood flow, and diuresis. Nevertheless, there is convincing evidence that a low dosage of dopamine is not only unable to prevent, reverse, or limit the progression of acute or ongoing renal failure, but its use, regardless of a clear assessment of the volemic status of the patient, may increase the risk of ARF. Dose dependent interactions on different receptors are not a clear cut-off value but represent the prevalence of activation of a group of receptors over another with a wide range of inter-individual variability. Thus, even a low dosage of dopamine” may exert a systemic vasocostrictory action without relevant improvement in renal function. A low dosage of dopamine may even jeopardize mucosal blood flow in the gut, suppress the function of the pituitary gland, interfer with cell mediated immunity, and impaire the thyroid function. The optimal selection of dopamine dosages is far less clear in critical care settings where an altered receptor function and responsiveness make the individual response unpredictable. Renal Effects As already reported, the era of dopamine, particularly “low dose dopamine” (LDD), began in 60’s when Goldberg described its effects on four patients affected by end stage congestive heart failure (Goldberg, McDonald Jr., & Zimmerman 1974). Drug administration, in doses ranging from 100 to 1,000g/min, increased cardiac output and sodium urinary excretion. This phenomenon occurred at lower doses, and with minimal impact on cardiovascular status. The same investigators showed that dopamine administration was able to increase plasmatic flow in the kidney, glomerulal filtration, and sodium excretion in healthy human subjects (McDonald 1964). In this study, the dose administered was titrated to achieve maximal renal effect without increasing mean arterial pressure. In 1965, the same authors investigated the renal effects of dopamine in anaesthetised dogs and concluded that dopamine might exert its action on particular receptors located in the kidneys (McNay, McDonald Jr., & Goldberg 1965). Twenty years after research by D’Orio et al. (1984), a series of dose response curves based on renal and haemodynamic effects observed in patients to whom different doses of dopamine were administered were observed. The dopamine suppressor dose was at that time defined as the dose at which dopaminergic and possibly adrenergic stimulation prevailed over adrenergic stimulation. This threshold corresponded to the infusion rate: < 5g/kg/min (D’Orio et al. 1984). Dopamine exerts its effects on the kidneys in dose dependent fashion. At low doses, such as 0, 3-5mcg/Kg/min, dopamine acts on D1 vascular receptors, which in turn increases renal blood flow. It appears that dopamine may additionally interact with D2 receptors located on presynaptic nerve endings, inhibiting the release of nor-epinephrine (Lee 1993). At higher doses, when adrenergic stimulation prevails, renal blood flow is augmented by the increase in cardiac output. Dopamine is able to induce diuresis and natriuresis by acting on both D1 and D2 receptors located on the proximal tubule, which is the thick ascending loop of the Henle and cortical collecting tubule. Those effects are achieved by the inhibition of Na+/K+-adenosine triphosphatase activity. In fact, it appears that the primary effect on renal epithelial cells is the removal of the plasma membrane of active Na+/K+ ATPase units. The net effect is the reduced capability of the tubular cells to Na+ transport (Bertorello & Sznajder 2005). Moreover, the stimulation of D2 receptors located on the collecting tubules of the inner medulla stimulates production of prostaglandin E2, (PGE2) which counterbalances the effects of antidiuretic hormones, augmenting the clearance of free water (Seri et al. 1988; Hubbard & Henderson 1995). The renal vasodilatory effects are associated with dose-dependent augmentation in renal blood flow and diuresis. LDD induces a redistribution of intraparenchymal renal blood flow towards the cortical region, counteracting the effect of PGE2 and shunting blood away from the outer medulla (Brezis et al. 1984). This can be harmful for two reasons. First, renal medulla has a limited blood supply. Second, it may promote a relative ischemia in a region that is high metabolically active and already works with a lower tension of oxygen. In fact, although the kidneys receive nearly 20 percent of cardia output, the greatest part of the blood flow supplies the outer parenchymal layers (Heyman, Fuchs, & Brezis 1995). For years LDD was a widely accepted therapeutic option to limit or prevent acute renal failure. Several investigations were carried out to assess the effects of LDD on renal function in critical patients who were at risk or had established renal failure. In some studies, LDD administration increased urine output; however, in others, no effect was found (D’Orio et al. 1984; Duke, Briedis, & Weaver 1994; Flancbaum, Choban, & Dasta 1994; Tang et al. 1999; Chertow et al. 1996). One study showed a potential negative effect of LDD dopamine administration on tubular function caused by the augmented urinary excretion of retinol binding protein in patients who had undergone coronary bypass surgery (Tang et al. 1999). Another paper showed that in post-cardiac surgery, patients with normal pre-operative renal function, dopamine was reported to increase renal oxygenation without increasing glomerular filtration rate, tubular sodium reabsorption, or renal oxygen consumption (Redfors et al. 2010). In fact, there is convincing evidence from literature that LDD not only is unable to prevent, reverse, or limit the progression of ARF, but its use, regardless of a clear assessment of the volemic status of the patients, may increase the risk of ARF. Moreover, a large prospective randomized study by the Australian and New Zealand Intensive Care Society Group showed that LDD not only was unable to prevent or reverse acute renal failure, but it failed to improve outcome variables. In fact, there were no differences in terms of mortality, need of renal replacement therapy, renal recovery, and peak serum creatinine among the patients. These findings confirmed the results of the retrospective analysis of the North American Septic Shock Trial (NORASEPT), where no reduction of the incidence of acute renal failure, the 28-day mortality, nor the requirement of haemodialysis were observed in septic patients who developed oliguria (Bellomo et al. 2000). In two recent meta-analyses about the impacts of LDD on ARF, the first by Kellum and Decker, dopamine did not prevent mortality, the onset of acute renal failure, or the need for haemodialysis (Kellum 2001). The second, by Marik, analysed 15 randomised controlled studies by comparing LDD administration with a placebo; there were no beneficial results in terms of serum creatinine change and the incidence of acute renal failure (Marik 2002). It has been argued by some authors that adding LDD in patients requiring norepinephrine may limit its adverse effects on renal circulation and function. Clear beneficial evidence on renal function of this therapeutic regime is lacking, as shown by studies carried out on experimental animal models and in patients with septic shock who require catecholamine administration. It is seems clear that LDD mediated increases in urinary output in septic shock patients, treated with norepinephrine, is probably mediated by the augmentation of cardiac output. A low dosage dopamine appears to be able to increase in urinary output in critically ill patients, but it doesn’t play any protective role against acute renal failure and does not improve the course of an established acute renal failure. When administered to critical patients, it may increase the risk of acute renal failure. Gut and Mesenteric Effects Gut has been considered as the “motor” of systemic inflammatory response syndrome (SIRS) (Hassoun et al. 2001). In fact, alterations of mesenteric blood flow and gut hypoperfusion represent the first response to hemodynamic derangements in critically ill patients when blood, pooled away from intestinal viscera, is redistributed to “vital” organs. This response causes intestinal hypoperfusion that facilitates the alteration of the barrier function and the increase of intestinal epithelial apopotosis (Han et al. 2004). In experimental models, dopamine increased both splanchnic ad hepatic blood flow. In another paper, this observation did not correlate with an improvement of mucosal perfusion. In a study on dogs, dopamine reduced intestinal blood flow, and in a porcine model, seemed to hasten gut ischemia. Those results seem to be due to the ability of DA to reduce blood flow to the mucosa by redistributing it within the gut. In another animal study, DA improved mucosal blood flow and oxygenation. Data regarding human studies shared the same deal of equivocal conclusion. In fact, some investigations showed that LDD can increase splanchnic blood flow in septic cardiac surgical patients, while others did not draw the same results. LDD seemed to decrease splanchnic oxygen consumption in septic patients in spite of an increase in splanchnic blood flow, and once again this effect was not confirmed in cardiac surgical patients. LDD increased oxygen transport in septic patients but led to a diminished gastric mucosal flow and did not affect pHi, a common and widely accepted marker of gut mucosal perfusion. The effect of DA administration seems to be at least partially dependent on the initial fractional splanchnic blood. Recently, De Backer et al. found no differences in PCO2 gap, splanchnic blood flow in their study, which was carried out on 20 septic patients. Moreover, dopamine administration showed a lower mixed venous-hepatic venous saturation gradient. DA 2 receptors are present in human enteric nervous endings, and dopamine administration may actually affect gastrointestinal motility. These effects have been confirmed both in healthy subjects who had undergone short-term DA administration, and in critically ill patients, in doses ranging from 2.5 to 5 μg/kg/min. Moreover, in another paper, LDD impaired gastroduodenal emptying in mechanically ventilated patient during fasting and nasogastric enteral feeding. Respiratory Effects As pointed out, DA administration may exert deleterious effects on respiratory functions. It impairs the ventilatory drive response to hypoxemia and hypercapnia by depressing the carotid body. It further reduces arterial oxygen saturation through a regional ventilation/perfusion mismatching. This does not represent a problem as long as patients are mechanically ventilated and an oxygen supplement is administered. Problems can arise during the weaning process from ventilatory support, when the physiological response to both hypoxia and hypercapnia might have been blunted by DA administration. LDD may favour weaning from the ventilator, but this comes at the expense of an actual risk of hastening respiratory failure. Endocrine and Immunological Effects Low doses of dopamine result in plasmatic levels up to 100 times higher than those generated by endogenous secretions, which may cause partial hypopituitarism in adults, infants, and children. In a work by Van den Berghe on 12 polytrauma patients, LDD dopamine administration lowered levels of thyroid stimulating hormones, thyroxine, and triiodothyronine. All values came back to normal after 24 hours from the suspension of DA. LDD infusion may trigger or exacerbate the euthyroid sick syndrome in critical illnesses. DA administration affected the secretion of the growth hormone (GH) in critically ill patients as pointed out by the same authors. GH pulsatile secretion is impaired in critically ill patients and it resulted further by being blunted by DA administration. The authors concluded that the suppression of GH secretion might enhance the catabolic process of critical illnesses. LDD dopamine has been show to suppress dehydroepiandrosterone (DHEAS) and prolactine levels in 20 critically ill patients. Cortisol levels were not affected. The levels of luteinizing hormone (LH) and testosterone were affected by dopamine administration in 15 critically ill men. LH rose after three hours from dopamine withdrawal, while testosterone levels failed to rebound. Dopamine receptors have been discovered on thymocytes, and dopamine is able to interact with lymphocytes. Dopaminergic agonist and dopamine suppress T- lymphocytes function and suppress T-cell functions in mice. In humans, specifically critically ill patients receiving dopamine, the drug was able to reduce the T-cells’ responsiveness Prolactine, whose levels have been shown to decrease under dopamine infusion, has immunoregolatory functions; B and T types have indeed prolactine receptors. The reduction of DHEAS has been advocated as a further cause of immune cellular response, because of lymphocyte T-helper and type 1-T lymphocyte induced dysfunction. Dopamine seems to affect the cellular mediated mechanism of the immune function directly by its action on receptors located on immune system cells and indirectly altering the hormonal response regulating immune response. Conclusion Dopamine is still used as a first line vasopressor agent in hypotensive patients. It does not offer protection from renal failure, even if the idea of a low dosage of dopamine gained widespread popularity and acceptance among critical care caregivers for years. The renal dose of dopamine is not predictable in humans who are critically ill. It can increase urine output and sodium excretion, but once again has no effects on the course of renal failure, requirements of renal replacement therapy, and mortality. Administration of LDD to inadequately fluid resuscitated and hemodinamically unstable patients can be harmful. After LDD administration, renal receptors seem to desensitize. Several studies were conducted on animals and humans and showed that the renal effects of LDD were lost after a variable period of time, anywhere from two to 48 hours. All of the studies concluded that there was no evidence to support sustained beneficial effects of DA administration. The effects of dopamine on gastrointestinal system and splanchnic perfusion are more controversial. It is well-recognized that an inadequate perfusion of the gut may be harmful, and have a role in the determinism of such feared clinical condition as the systemic inflammatory syndrome. There is no clear evidence of which vasoactive agent is the best for preserving regional gut perfusion. Several papers pointed out the detrimental effects of dopamine. In a recent study, however, dopamine appeared to have in septic shock of moderate severity a “slightly better profile” on splanchnic circulation. This matter deserves further investigation. Over the years, dopamine has been the first line vasopressor in hypotensive status refractory to fluid resuscitation because of the feared ischemic side effects of norepinephrine on end organ perfusion. Recent evidence has shown that norepinephrine administration can effectively restore an adequate hemodynamic status in adequately fluid resuscitated patients. The use of norepinephrine has been shown to have a protective effect on renal blood flow and to increase diuresis in animal and human septic shock conditions. Moreover there are data suggesting that norepinephrine does not impair splanchnic circulation in animal models of endotoxin shock and in septic patients. On the contrary, norepinephrine was associated with a greater increase in pHi as compared to dopamine in septic shock patients. Again, dopamine (4g/kg/min) reduced hepatosplanchnic oxygen uptake in spite of an increase in systemic and regional perfusion. This effect was not shared by dobutamine. Of even greater interest are the results of the SOAP study, which were in a recent publication. Dopamine administration in shock patients was associated with an ICU and 20 percent higher hospital mortality rates, as compared to patients who did not receive it. Interestingly, in this study, dopamine was the first line drug for the treatment of septic shock. Dopamine “owes” its popularity to the work of Goldberg. Over the years, renal and splanchnic protective effects have been challenged and not confirmed at all. There is no equivocal conclusion about its effects on gut, but DA has been proven to cause major disturbances in anterior pituitary function and the immune system. Dopamine may further impair muscular blood supply. We can conclude that low dose dopamine for renal protection is no longer justified and should be definitely abandoned. Its use as a first choice vasopressor should be questioned in view of its potentially deleterious side effects and the increased rate of mortality associated with its administration in septic patients. Bibliografia 1. Goldberg, L.I., R.H. McDonald, Jr., and A.M. Zimmerman, Sodium Diuresis Produced by Dopamine in Patients with Congestive Heart Failure. N Engl J Med, 1963. 269: p. 1060-4. 2. McDonald, R.H., Jr., et al., Effect of Dopamine in Man: Augmentation of Sodium Excretion, Glomerular Filtration Rate, and Renal Plasma Flow. J Clin Invest, 1964. 43: p. 1116-24. 3. McNay, J.L., R.H. McDonald, Jr., and L.I. Goldberg, Direct Renal Vasodilatation Produced by Dopamine in the Dog. Circ Res, 1965. 16: p. 510-7. 4. DOrio, V., et al., The use of low doses of dopamine in intensive care medicine. Arch Int Physiol Biochim, 1984. 92(4): p. S11-20. 5. Lee, M.R., Dopamine and the kidney: ten years on. Clin Sci (Lond), 1993. 84(4): p. 357-75. 6. Bertorello, A.M. and J.I. Sznajder, The dopamine paradox in lung and kidney epithelia: sharing the same target but operating different signaling networks. Am J Respir Cell Mol Biol, 2005. 33(5): p. 432-7. 7. Seri, I., et al., Locally formed dopamine inhibits Na+-K+-ATPase activity in rat renal cortical tubule cells. Am J Physiol, 1988. 255(4 Pt 2): p. F666-73. 8. Hubbard, P.C. and I.W. Henderson, Renal dopamine and the tubular handling of sodium. J Mol Endocrinol, 1995. 14(2): p. 139-55. 9. Brezis, M., et al., Renal ischemia: a new perspective. Kidney Int, 1984. 26(4): p. 375-83. 10. Heyman, S.N., S. Fuchs, and M. Brezis, The role of medullary ischemia in acute renal failure. New Horiz, 1995. 3(4): p. 597-607. 11. Duke, G.J., J.H. Briedis, and R.A. Weaver, Renal support in critically ill patients: low-dose dopamine or low-dose dobutamine? Crit Care Med, 1994. 22(12): p. 1919-25. 12. Flancbaum, L., P.S. Choban, and J.F. Dasta, Quantitative effects of low-dose dopamine on urine output in oliguric surgical intensive care unit patients. Crit Care Med, 1994. 22(1): p. 61-8. 13. Tang, A.T., et al., The effect of renal-dose dopamine on renal tubular function following cardiac surgery: assessed by measuring retinol binding protein (RBP). Eur J Cardiothorac Surg, 1999. 15(5): p. 717-21; discussion 721-2. 14. Chertow, G.M., et al., Is the administration of dopamine associated with adverse or favorable outcomes in acute renal failure? Auriculin Anaritide Acute Renal Failure Study Group. Am J Med, 1996. 101(1): p. 49-53. 15. Redfors, B., et al., Dopamine increases renal oxygenation: a clinical study in post-cardiac surgery patients. Acta Anaesthesiol Scand, 2010. 54(2): p. 183-90. 16. Bellomo, R., et al., Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet, 2000. 356(9248): p. 2139-43. 17. Kellum, J.A. and M.D. J, Use of dopamine in acute renal failure: a meta-analysis. Crit Care Med, 2001. 29(8): p. 1526-31. 18. Marik, P.E., Low-dose dopamine: a systematic review. Intensive Care Med, 2002. 28(7): p. 877-83. 19. Hassoun, H.T., et al., Post-injury multiple organ failure: the role of the gut. Shock, 2001. 15(1): p. 1-10. 20. Han, X., et al., Increased iNOS activity is essential for intestinal epithelial tight junction dysfunction in endotoxemic mice. Shock, 2004. 21(3): p. 261-70. Read More