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Vaso-Active Agents in the Emergency Department Michael C. Bond, MD Objectives 1. Review the definition of SIRS and Shock 2. Review the different classifications of shock 3. Review vasopressors and their mechanisms of action a. Dopamine b. Dobutamine c. Epinephrine d. Norepinephrine e. Phenylephrine f. Vasopressin 4. Review the pathophysiology of septic shock and current treatment Systemic Inflammatory Response Syndrome 1. Any two or more of the following are present a. Heart rate > 90 beats per minute b. Body temperature < 36 or > 38°C c. Hyperventilation (high respiratory rate) > 20 breaths per minute or, on blood gas, a PaCO2 < 4.3 kPa (32 mm Hg) d. White blood cell count < 4000 cells/mm3 or > 12000 cells/mm3 (< 4 x 109 or > 12 x 109 cells/L), or the presence of greater than 10% immature neutrophils. Causes of SIRS 1. Severe trauma 2. Surgery, complication of 3. Burns 4. Acute pancreatitis 5. Immunodeficiency (such as AIDS) 6. Infection SIRS versus Sepsis SIRS with a confirmed infection, proven through a positive blood culture or tissue sample positive for pathogenic organisms, is called sepsis. Shock Definition: 1. Inadequate tissue perfusion that impairs cellular metabolism 2. Oxygen Supply < Oxygen Demand 3. SBP<90 mm Hg or a reduction of ≥40 mm Hg from baseline along with the presence of perfusion abnormalities Phenylephrine 1. Raises blood pressure and as a pure alpha agonist should not cause tachycardia. 2. Most commonly used in neurogenic shock (IE spinal cord injury or spinal anesthesia) 3. Works by increasing systemic vascular resistance with no effect on the heart. 4. Phenylephrine 5. Typically a second line agent in sepsis due to its tendency to reduce cardiac output. 6. A decrease in splanchnic blood flow, oxygen delivery and lactate uptake was observed in patients that were switched from norepinephrine to phenylephrine. Dopamine 1. Often first line treatment for hypotension. 2. Mixed inotropy and vasoconstrictor. a. Predominantly beta adrenergic effects in low to moderate dose ranges (up to 10 mic/kg/min). b. This effect may be due to it’s conversion to norepinephrine in the myocardium, and activation of adrenergic receptors. c. In higher dose ranges, alpha adrenoceptor activation increase and causes vasoconstriction. d. At all dose ranges it is a potent chronotrope. 3. The so-called “renal protective” effect appears to be a misnomer. a. Real Effect is probably: b. An increase in cardiac output, due to inotropy, and thus renal perfusion pressure. c. A direct diuretic action. d. No evidence that dopamine, at low dose, protects or harms the kidneys. Dobutamine 1. Potent beta-1 agonist, increases myocardial contractility and thus stroke volume and cardiac output. a. Associated with much less increase in heart rate than dopamine. b. Has a vasodilatory effect, so about 1/3 patients will have a decrease in MAP with the initiation of dobutamine. 2. In sepsis, increases oxygen delivery and consumption. 3. Dobutamine appears particularly effective at splanchnic resuscitation, increasing pHi (gastric mucosal pH) and improving mucosal perfusion in comparison with dopamine. Epinephrine 1. It remains the agent of choice when patients are in-extremis – such as in anaphylactic shock or cardiac arrest. 2. Otherwise, second line agent due to: a. It increase myocardial oxygen demand. b. It increases serum lactate – this may be due to either worsening of perfusion to certain tissues, or due to a calorigenic effect (increased release and anaerobic breakdown of glucose). 3. Epinephrine appears to have adverse effects on splanchnic blood flow. 4. The increase in mean arterial pressure in sepsis is mainly from an increase in cardiac output (stroke volume). Norepinephrine 1. In low dosage ranges, the beta effect is noticeable, and there is a mild increase in cardiac output. In most dosage ranges, vasoconstriction and increased mean arterial pressure are evident. 2. Does not increase heart rate: its effects on MAP may actually reduce heart rate as a result of baroreceptor activation. 3. The main beneficial effect is to increase organ perfusion by increasing vascular tone. 4. Unlike epinephrine, norepinephrine reduces serum lactate levels. 5. Most effective at splanchnic resuscitation if used in combination with dobutamine. Vasopressin 1. Second line vasoconstrictor in septic patients 2. Appears to be a quantitative deficiency of this hormone in sepsis 3. Most efficacious dose appears to be 0.04units/min 4. No pH dependence 5. Effects on splanchnic perfusion and the extremities are probably adverse (remember that vasopressin has traditionally been used to reduce splanchnic blood flow, in the treatment of bleeding esophageal varices), particularly as the dose escalates. Comparison of Vasopressors 1. Comparison of dopamine to dobutamine and norepinephrine for oxygen delivery and uptake to septic shock. Critical Care Medicine 1995:23(12); 1962-1970 a. Increased oxygen delivery though oxygen uptake did not change. b. The oxygen extraction ratio decreased significantly. c. Primary effect of dopamine seemed to be an increase in cardiac index, with little effect on systemic vascular resistance. 2. The contrasting effects of Dopamine and Norepinephrine on Systemic and Splanchnic Oxygen Utilization in Hyperdynamic Sepsis. JAMA 1994:272(17); 1354-1357. a. Dopamine increased MAP by increasing cardiac index b. Dopamine increased oxygen delivery and oxygen consumption c. Dopamine significantly decreased the gastric intramucosal pH (sign of inadequate resuscitation) 3. The effect of Vasopressin on Gastric Perfusion Catecholamine-Dependent Patients in Septic Shock. Chest 2004; 124:2256-2260. a. Low dose vasopressin 0.04 units/min added to Norepi or Epi b. They did not change Norepi or Epi when Vasopressin was added unless MAP < 50 mm Hg c. MAP increased with Vasopressin but there was no change in cardiac index d. Significant increase in P(g-a)CO2 gap compatible with GI hypoperfusion when Vasopressin added. 4. Schleien CL, Osmond MH, Hickey R, et al. Postresusciatation Management. Ann Emerg Med. April 2001;37:S182-S195. a. Avoid use of dopamine (high dose) as a single-agent vasopressor in hypotensive patients. b. If hypotension persists after filling pressure is optimized, inotropic (dobutamine), vasopressor (norepinephrine), or vasodilator (nitroprusside or nitroglycerin) therapy may be indicated. 5. Dunser MW, Mayr AJ, Ulmer H, et al. Arginine Vasopressin in Advanced Vasodilitatory Shock, A Prospective, Randomized, Controlled Study. Circulation. 2003; 107:2313-2319. a. Compared Vasopressin & Norepinephrine to Norepinephrine only. b. 48 critically ill patients c. Vasopressin at 4 U/h. (0.06 units/min) d. Norepinephrine titrated to maintain MAP ≥ 70 e. MAP, CI, Stroke Volume Index, and LV Stroke Work index all significantly higher in Vasopressin Patients f. Norepinephrine only patients more likely to develop tachycardia. g. Gastric Tonometry was better preserved in Vasopressin treated patients. Vasopressor Conclusions 1. Norepinephrine a. Ideal for Septic Shock b. Increases vascular tone c. More potent than dopamine d. Increased cardiac contractility, and cardiac output e. Decreased risk for tachycardia f. No effect on the hypothalamic-pituitary axis g. Observational Study has shown that survival advantage in septic shock. h. (62% vs 82% Mortality) 2. Dobutamine should be added to Norepinephrine if additional cardiac output is needed Early Goal Directed Therapy 1. Goals a. Maintain a CVP between 8 – 12 mmHG b. Mean arterial blood pressure 65 mmHG c. CvO2 > 70% 2. If patient received adequate fluid resuscitation and CvO 2 still <70% a. Transfusion of packed red blood cells for HCT>30% b. Dobutamine therapy started 3. Patients improved in the EGT group 4. Rhodes A, Bennett ED. Early goal-directed therapy: An evidence-based review. Critical Care Medicine 2004; 32 (Suppl.):S448-S450. a. Specific targets that should be reached during the first 6 hours of resuscitation are: i. Central Venous Pressure (8-12 mm Hg) ii. Mean Arterial Pressure ≥ 65 mm Hg iii. Urine Output of ≥ 0.5 ml/kg/hr iv. SvO2 ≥ 65% or ScO 2 ≥ 70% b. If these targets can not be reached you should i. Transfuse packed red blood cells to achieve HCT ≥ 30% ii. Administer dobutamine infusion (up to a maximum of 20 mcg/kg/min) 5. Trzeciak S, Dellinger RP, Abate NL. A 1-Year Experience with implementing Early Goal-Directed Therapy for Septic Shock in the Emergency Department. Chest 2006; 129:225-232. a. All end points achieved in 20 of 22 cases b. EGDT was associated with decreased ICU pulmonary artery catheter use (9.1% vs. 43.7%) c. Volume Infused went from 3.5 L to 5.6 L in the ED, and 9L to 7.9 for first 24 hours. Summary 1. Low dose dopamine should NOT be used for renal protection. 2. Norepinephrine has better outcomes than dopamine with no affect on dopamine receptors in the brain 3. Phenylephrine and Epinephrine should not be used as first line agents in septic shock. 4. Dobutamine is the agent of choice to increase cardiac output, and it should not be used to increase cardiac output above physiologic levels. 5. Vasopressin should be a second line agent due to the effects it might have on splanchnic blood flow. References: Reinelt H, Radermacher P, Kiefer P, Fischer G, Wachter U, Vogt J et al. Impact of exogenous beta-adrenergic receptor stimulation on hepatosplanchnic oxygen kinetics and metabolic activity in septic shock. Critical Care Medicine 1999; 27(2):325-331. Comparison of dopamine to dobutamine and norepinephrine for oxygen delivery and uptake to septic shock. Critical Care Medicine 1995;23(12): 1962-1970 The contrasting effects of Dopamine and Norepinephrine on Systemic and Splanchnic Oxygen Utilization in Hyperdynamic Sepsis. JAMA 1994:272(17); 1354-1357. Low Dose Dopamine: What Benefit? Critical Care Medicine 2000; 28 (3); 907-908. Neviere R, Mathieu D, Chagnon JL, Lebleu N, Wattel F. The contrasting effects of dobutamine and dopamine on gastric mucosal perfusion in septic patients. Am J Respir Crit Care Med 1996; 154(6 Pt 1):1684-1688. Kellum JA, Pinsky MR. Use of vasopressor agents in the critically ill patients. Current Opinion in Critical Care 2002; 8:236-241. Holmes CL. Vasoactive drugs in the intensive care unit. Current Opinion in Critical Care 2005;11:413-417. De Backer D, Creteur J, Silva E, et al. Effect of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: Which is best? Critical Care Medicine 2003; 31(6): 1659-1667. Klinzing S, Simon M, Reinhart K, et al. High-dose vasopressin is not superior to norepinephrine in septic shock. Critical Care Medicine 2003; 31(11): 2646-2650. Woolsey CA, Coopersmith CM. Vasoactive drugs and the gut: is there anything new? Current Opinion in Critical Care 2006; 12:155-159. Van Haren FMP, Rozendaal FW, van der Hoeven JG. The effect of Vasopressin on Gastric Perfusion Catecholamine-Dependent Patients in Septic Shock. Chest 2004; 124:2256-2260. Schleien CL, Osmond MH, Hickey R, et al. Postresusciatation Management. Ann Emerg Med. April 2001;37:S182-S195. Dunser MW, Mayr AJ, Ulmer H, et al. Arginine Vasopressin in Advanced Vasodilitatory Shock, A Prospective, Randomized, Controlled Study. Circulation. 2003; 107:2313- 2319. Rhodes A, Bennett ED. Early goal-directed therapy: An evidence-based review. Critical Care Medicine 2004; 32 (Suppl.):S448-S450. Trzeciak S, Dellinger RP, Abate NL. A 1-Year Experience with implementing Early Goal-Directed Therapy for Septic Shock in the Emergency Department. Chest 2006; 129:225-232. Otero RM, Nguyen HB, Huang DT, Rivers EP, et al. Early Goal-Directed Therapy in Severe Sepsis and Septic Shock Revisted. Concepts, Controversies, and Contemporary Findings. Chest 2006; 130:1579-1595. Herbert PC et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. NEJM. 349(6):409-417. 1999. Marik PE, Sibbald WJ. Effects of stored-blood transfussion on oxygen delivery in patients with sepsis. JAMA 1993; 269:3024-3029.
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