The effects of milrinone on hemodynamics in an experimental septic shock model Jean-Michel Liet, MD, MSc; Cédric Jacqueline; Jean-Luc Orsonneau, MD; Christèle Gras-LeGuen, MD; Gilles Potel, MD; Jean-Christophe Rozé, MD M ilrinone is a type III phos- phodiesterase inhibitor that increases contractility and improves diastolic function by decreasing the degradation of cyclic adenosine monophosphate and in- creasing intracellular calcium release (1). Additionally, this non- -adrenergic mechanism decreases intracellular cal- cium in vascular smooth muscle and leads to vasodilation. Administration of milrinone is beneficial in infants and children after corrective surgery for con- genital heart disease (2, 3). Pediatric in- terventional studies show that milrinone (4) and amrinone (5) improve cardiovas- cular function in patients with septic shock. Beneficial effects of milrinone were observed in patients with meningo- coccal sepsis and severe purpura with va- soconstriction that involved the risk of peripheral necrosis (6). Enoximone, an- other type III phosphodiesterase inhibi- tor, can immediately restore myocardial contractility in patients with severe pro- longed catecholamine and volume-refrac- tory endotoxin shock associated with Wa- terhouse-Friderichsen syndrome, even in cases involving complete myocardial ar- rest (7). However, the effects of these drugs were only observed while the children were already receiving catecholamine support. As a result of the hazard of hy- potension, guidelines pertaining to the treatment of cases involving septic shock restrict the use of milrinone for pediatric patients, who remain in a state of normo- tensive low cardiac output and high vas- cular resistance despite receiving epi- nephrine and nitrovasodilator therapy (8). Our aim was to investigate the spe- cific hemodynamic effects of milrinone in an animal model of septic shock in the absence of any other treatment, and to study the hazard of vasodilatation and hypotension after infusion of milrinone to widen the implications of the use of milrinone in cases involving septic shock. MATERIALS AND METHODS Animal Preparations. This study used 14 female New Zealand white rabbits (weight, 2.4 –3.2 kg) that were housed in individual cages with free access to food and water. The rabbits were anesthetized with ketamine (in- tramuscularly at 20 mg/kg), and the anesthe- sia was administered continuously throughout the study by intravenous infusion of ketamine (4 mg/kg/hr) through the marginal vein of the left ear. A warming lamp was used to maintain the animal’s blood temperature above 38°C. Once anesthetized, a catheter was inserted into the internal jugular vein for fluid (4 mL/ kg/hr with a saline solution) and drug admin- istration. The femoral artery was cannulated with a thermodilution catheter (4 Fr, 8 cm, with lumen for arterial pressure, Pulsiocath PV2014L08; Pulsion Medical Systems, Mu- nich, Germany). The protocol used for animal care and use was reviewed and approved by the University of Nantes Animal Resources Center. Hemodynamic Measurements. Mean arte- rial blood pressure (MAP) was monitored con- tinuously. Cardiac index (CI) was determined every 30 mins by a transpulmonary thermodi- lution technique using an integrated monitor- From the Pediatric Intensive Care Unit (JML, CGL, JCR) and the Department of Medical Biochemistry (JLO), University Hospital of Nantes, Nantes, France, UPRES EA 1156: Thérapeutiques Cliniques et Expéri- mentales des Infections, University of Nantes, Nantes, France. All authors have no financial interests to disclose. Copyright © 2005 by the Society of Critical Care Medicine and the World Federation of Pediatric Inten- sive and Critical Care Societies DOI: 10.1097/01.PCC.0000155636.53455.96 Objective: To investigate the specific hemodynamic effects of the phosphodiesterase inhibitor milrinone in a rabbit model of septic shock in the absence of any other treatment. Design: A prospective, controlled, interventional study. Animal Model: Fourteen sedated New Zealand rabbits. Setting: Research laboratory of a health sciences university. Interventions: Rabbits were anesthetized and vascular cathe- ters inserted in femoral artery and jugular vein. After a stabiliza- tion period and the recording of baseline measurements (H0), all animals received a 10-mL infusion of Pseudomonas aeruginosa. Two hours later (H2rabbits were randomly assigned to receive 5% dextrose (control group) or milrinone (milrinone group). Measurements and Main Results: Mean arterial blood pressure (MAP) was monitored continuously, and a cardiac index (CI) was determined every 30 mins by a transpulmonary thermodilution tech- nique using an integrated monitoring device (PICCO). No differences were detected between the two groups after stabilization (H0) or before the treatment (H2) for either CI (mL/min -1 /kg -1 ) or MAP (mm Hg). CI decreased progressively in the control group during the following 4 hrs, but not in the treated group (at H6: 122  4 vs. 207  16 mL/min -1 /kg -1 ; p < .05). No drop of MAP occurred after milrinone infusion. A comparison of the treated and control group reveals that milrinone improved tissue perfusion as evidenced by measurements of central venous saturation (at H4: 0.59  0.05 vs. 0.71  0.03, p  .04), lactacidemia (at H6: 10.3  2.4 vs. 3.9  0.9 mmol/L, p  .03), creatinemia (at H6: 95  11 vs. 60  5 mol/L, p  .02) and survival (at H6: 5 vs. 7, not significant). Conclusion: Milrinone improves cardiac output and tissue per- fusion in a rabbit model involving severe septic shock. (Pediatr Crit Care Med 2005; 6:195–199) KEY WORDS: milrinone; hemodynamics; shock; sepsis; phospho- diesterase inhibitor 195 Pediatr Crit Care Med 2005 Vol. 6, No. 2