e6 tive, double blinded, randomized, placebo controlled, interven tional study Chest 1996;109(5) 1302 1312 238 Young RA, Ward A Milrinone A preliminary review of its pharma cological properties and th[.]
e6 tive, double-blinded, randomized, placebo-controlled, interventional study Chest 1996;109(5):1302-1312 238 Young RA, Ward A Milrinone A preliminary review of its pharmacological properties and therapeutic use Drugs 1988;36(2):158-192 239 Edelson J, Stroshane R, Benziger DP, et al Pharmacokinetics of the bipyridines amrinone and milrinone Circulation 1986;73(3 Pt 2): III145-III152 240 Sandor GG, Bloom KR, Izukawa T, et al Noninvasive assessment of left ventricular function related to serum digoxin levels in neonates Pediatrics 1980;65(3):541-546 241 Bailey JM, Miller BE, Lu W, et al The pharmacokinetics of milrinone in pediatric patients after cardiac surgery Anesthesiology 1999;90(4):1012-1018 242 Ramamoorthy C, Anderson GD, Williams GD, et al Pharmacokinetics and side effects of milrinone in infants and children after open heart surgery Anesth Analg 1998;86(2):283-289 243 Das PA, Skoyles JR, Sherry KM, et al Disposition of milrinone in patients after cardiac surgery Br J Anaesth 1994;72(4):426-429 244 Lindsay CA, Barton P, Lawless S, et al Pharmacokinetics and pharmacodynamics of milrinone lactate in pediatric patients with septic shock J Pediatr 1998;132(2):329-334 245 Gist KM, Goldstein SL, Joy MS VA Milrinone dosing issues in critically ill children with kidney injury: a review J Cardiovasc Pharmacol 2016;67(2):175-181 246 Chu CC, Lin SM, New SH, et al Effect of milrinone on postbypass pulmonary hypertension in children after tetralogy of Fallot repair Zhonghua Yi Xue Za Zhi (Taipei) 2000;63(4):294-300 247 McEvoy GK, ed Milrinone lactate In: AHFS Drug Information Bethesda, MD: Association of Health-System Pharmacists; 2009 248 Primacor Physician’s Desk Reference Montvale, NJ: Thomson; 2003 249 Mizuno T, Gist KM, Gao Z, et al Developmental pharmacokinetics in age-appropriate dosing design of milrinone in neonates and infants with acute kidney injury following cardiac surgery Clin Pharmacokinet 2019;58(6)793-803 250 Akkerman SR, Zhang H, Mullins RE, et al Stability of milrinone lactate in the presence of 29 critical care drugs and i.v solutions Am J Health Syst Pharm 1999;56(1):63-68 251 Veltri MA, Conner KG Physical compatibility of milrinone lactate injection with intravenous drugs commonly used in the pediatric intensive care unit Am J Health Syst Pharm 2002;59(5):452-454 252 Smith AH, Owen J, Borgman KY, et al Relation of milrinone after surgery for congenital heart disease to significant postoperative tachyarrhythmias Am J Cardiol 2011;108(11):1620-1624 253 Held P, Rosenqvist M, Rydén L, et al Pharmacological treatment of heart failure Lakartidningen 1992;89(35):2755-2758 254 Lewis RP Digitalis: a drug that refuses to die Crit Care Med 1990; 18(1 Pt 2):S5-S13 255 McEvoy GK, ed Digoxin In: AHFS Drug Information Bethesda, MD: American Society of Health-System Pharmacists; 2009 256 Ratnapalan S, Griffiths K, Costei AM, et al Digoxin-carvedilol interactions in children J Pediatr 2003;142(5):572-574 257 Iseri LT, Freed J, Bures AR Magnesium deficiency and cardiac disorders Am J Med 1975;58(6):837-846 258 Smith TW, Butler VP, Haber E, et al Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: experience in 26 cases N Engl J Med 1982;307(22):1357-1362 259 EL Desoky ES, Nagaraja NV, Derendorf H Population pharmacokinetics of digoxin in Egyptian pediatric patients: impact of one data point utilization Am J Ther 2002;9(6):492-498 260 Hougen TJ Digitalis use in children: an uncertain future Prog Pediatr Cardiol 2000;12(1):37-43 e7 Abstract: Cardiovascular dysfunction is a cardinal manifestation of critical illness in children Pediatric intensivists must have a solid understanding of the basic science and practice aspects of drugs used to treat these disorders Therefore, a thorough understanding of cardiovascular pharmacology—including the indications, clinical effects, pharmacokinetics, pharmacodynamics, adverse reactions, and drug interactions—is essential to ensure optimal outcomes with minimal risk This chapter offers an overview of the clinical pharmacology of the five catecholamines, two noncatecholamine agents, and the venerable cardiac glycosides most commonly used to support critically ill children Key words: Shock, vasoactive drugs, adrenergic receptors, catecholamines, epinephrine, norepinephrine, inotropes, bipyridines, milrinone, phosphodiesterase inhibitor, vasopressin 32 Cardiopulmonary Interactions RONALD A BRONICKI, MUBBASHEER AHMED, SAUL FLORES, AND BRADLEY P FUHRMAN • • • Positive-pressure ventilation (PPV) alters ventricular loading conditions and compliance In patients who are hypovolemic, the effects of positive airway pressure on the right heart predominate, whereas in patients who have systemic ventricular systolic dysfunction, the effects of PPV on left ventricular (LV) afterload predominate Large changes in arterial pulse pressure over the respiratory cycle help to identify mechanically ventilated patients who may • • PEARLS have a favorable response to the administration of fluid or who may not tolerate high levels of positive end-expiratory pressure without fluid administration PPV raises juxtacardiac pressure, thereby reducing LV afterload Respiratory effort imposes critical loads on the heart, and respiratory muscle failure from inadequate oxygen delivery (DO2) is a final common pathway to death from shock Both spontaneous breathing and positive-pressure ventilation (PPV) affect the circulation in predictable ways The cardiovascular system also has important effects on respiration, ventilation, and gas exchange preponderant effects on the circulation, and are mediated by changes in intrathoracic pressure (ITP) and venous return over the respiratory cycle Spontaneous breathing and PPV have opposite effects on ITP, which largely explains their different effects on CO Effects of Ventilation on Circulation Systemic Venous Return The mean systemic pressure of the circulation (Pms) is thought to be the inflow pressure driving blood toward the right atrium.2 This driving pressure is not measurable in the intact patient, but it can be thought of as the static mean pressure that might exist throughout the circulation if there were instantaneously no blood flow.3 Pms approximates the weighted average of pressures in venous reservoirs throughout the body during the circulation of blood.4 The backpressure that opposes systemic venous return is the right atrial pressure (Pra) The impact of these pressures on the return of venous blood to the heart is described by the venous return curve (Fig 32.1A), which is drawn in such a way that the independent variable (Qpump) appears on the y-axis Picture the systemic circulation as composed of noncompliant arteries functioning largely as conductive vessels and venous reservoirs functioning as capacitive vessels, which are separated by highresistance arterioles and a pump that receives venous return and propels it into the systemic arterial circulation (Fig 32.1B) The faster the pump circulates the blood, the more blood piles up before the arterioles and the higher the arterial pressure will be; the faster the pump moves blood from venous to arterial system, the less blood resides on the venous side of the circuit and the lower the Pra will be (x-axis) As the pump is slowed down, venous pressure rises until flow reaches zero, at which point vascular pressures equilibrate throughout the circulation at Pms Resistance to venous return (Rvr) is the reciprocal of the slope of the linear part of the venous return curve Simply stated, As shown by Cournand et al.1 in their seminal study, PPV can have important effects on the circulation The magnitude of these effects may be accentuated by factors that compromise cardiovascular homeostatic responsiveness, such as hypovolemia, cardiac dysfunction, or disordered vascular tone PPV alters ventricular loading conditions and compliance These interactions may occur simultaneously and yet not act in the same direction on cardiac output (CO) The net effect on CO depends on which interactions predominate over the course of the respiratory cycle and on underlying cardiopulmonary function For this reason, it is often easier to rationalize an interaction than to predict it For clarity of discussion, wherever the terms positive pressure or mechanical ventilation are used in this chapter, the patient is presumed to respond passively, as though subjected to neuromuscular blockade In general, the term preload dependence is used in this chapter to connote patients in whom the dominant cardiovascular effect of positive pressure breathing is to reduce right heart filling with resultant fall in stroke volume Afterload dependence is the term applied to identify patients whose dominant effect is afterload reduction and consequent increase in stroke volume Right Ventricular Filling and Stroke Volume The effects of PPV on filling of the right heart are the best understood of the various heart-lung interactions, are generally the 320 CHAPTER 32 Cardiopulmonary Interactions these pressures (pleural, juxtacardiac, and right atrial) are influenced by the respiratory cycle.6–8 During spontaneous breathing, lung volume rises from FRC to end-inspiratory volume by expansion of the rib cage and descent of the diaphragm This reshaping of the thorax stretches the lung, increasing its recoil tension, so that pleural pressure and juxtacardiac pressure both become more negative (subambient) At any right atrial volume, spontaneous inspiration reduces Pra by increasing its transmural pressure (Ptm, inside—surrounding or juxtacardiac pressure), which distends the compliant chamber, causing the pressure within to fall By the mathematic relationship in Eq 32.1, this augments venous return.9 Over the course of passive spontaneous expiration, all three pressures return to their values at FRC It follows that ITP, during relaxed, spontaneous breathing, is always most negative at end-inspiration and becomes progressively less negative throughout the rest of the respiratory cycle Qpump Qmax Pc Veins Pra Pump oxygenator Pms Arteries Ca Cv B Right Ventricular Preload and Stroke Volume Peripheral resistance • Fig 32.1 (A) Systemic venous return curve Flow (Qpump ) is plotted on the ordinate but is treated as the independent variable Right atrial pressure (Pra ), the dependent variable, is plotted on the abscissa (B) Circulation is treated as though a pump transferred blood from veins to arteries, generating arterial pressure sufficient to overcome peripheral arterial resistance Arterial compliance (Ca ) and venous compliance (Cv ) determine the volume of blood distending arteries and veins at any Qpump When there is no flow, pressure equilibrates throughout the circulation at the mean systemic pressure of the circulation (Pms ) As pump flow is progressively increased, venous pressure falls and arterial pressure rises because of the net transfer of blood from veins to arteries by the pump and because of the accumulation of blood before the peripheral resistance When venous pressure falls to Pc, the critical closing pressure of the venous system, no further increase in pump flow is possible (Modified from Guyton AC Determination of cardiac output by equating venous return curves with cardiac response curves Physiol Rev 1955;35:123.) Venous Return ( Pms Pra ) R vr Eq 32.1 X X X XX X gh X X od o bl l vo e o bl um w Lo od e m lu vo Pms is a function of intravascular volume and vascular compliance, the vast majority of which reside within and with the venous reservoirs, respectively The Pms can be altered by changes in venous tone and intravascular volume Pms is an extrathoracic measurement and is less sensitive than Pra to changes in ITP.5 Pra, in contrast, is quite sensitive to changes in ITP At functional residual capacity (FRC), the thorax exerts recoil force, tending to spring outward, whereas the lung exerts recoil force (mostly as a result of alveolar surface tension), tending to collapse inward These forces result in subambient pleural pressure The cardiac fossa, or juxtacardiac space, which surrounds the pericardium and heart, shares in this balance of forces and has slightly negative pressure at apneic FRC At any right atrial volume, Pra is influenced by juxtacardiac pressure because these two forces act together to oppose the right atrium’s balloon-like tendency to recoil inward Therefore, it is not surprising that all of X X Hi During spontaneous inspiration, systemic venous return to the right atrium increases In addition, during ventricular diastole, the right ventricular (RV) Ptm increases as the juxtacardiac pressure decreases, increasing its effective compliance and, for a given diastolic pressure, the extent to which it fills The same principle applies to the left ventricle (LV) Despite a fall in right atrial and RV diastolic pressures (they are equal in the absence of tricuspid valve stenosis), the Ptm increases during spontaneous inspiration and RV filling and stroke volume increase Hence, there is a seemingly paradoxical inverse relationship between Pra and RV stroke volume over the spontaneous respiratory cycle (Fig 32.2).10 However, if right atrial Ptm is plotted against RV stroke volume during various respiratory maneuvers and with expansion of intravascular volume, the expected strongly positive relation is found (Fig 32.3).11 RV stroke volume (mL) A 321 Pra (mm Hg) • Fig 32.2 During spontaneous inspiration, right atrial pressure (Pra ) falls, but this decline is associated with an increase in right ventricular stroke volume shown at two different blood volumes Beat-by-beat values for stroke volume (noted by X’s) are superimposed on venous return curves (Modified from Pinsky MR Instantaneous venous return curves in an intact canine preparation J Appl Physiol 1984;56:765.) 322 S E C T I O N I V Pediatric Critical Care: Cardiovascular Müller maneuver Volume load Spontaneous breathing Positive pressure breathing Valsalva maneuver Pleural pressure SVrv (mL) Positive pressure ventilation Insp Exp Ppl at FRC Spontaneous breathing • Fig 32.4 Over the course of the respiratory cycle, if spontaneous and positive pressure breaths both begin and end at the same functional residual capacity (FRC), spontaneous breathing takes place at lower pleural pressure than does positive-pressure ventilation Exp, Expiration; Insp, inspiration; Ppl, pleural pressure Pra transmural (mm Hg) • Fig 32.3 Over a wide range of respiratory maneuvers, right ventricular stroke volume (SVrv ) varies directly with transmural right atrial pressure (Pra), as might be anticipated from the superimposed Starling curve (Modified from Pinsky MR Determinants of pulmonary arterial flow variation during respiration J Appl Physiol 1984;56:1237.) Positive Pressure Ventilation and Right Ventricular Preload The effects of PPV on pleural, juxtacardiac, and Pra are opposite those of spontaneous breathing A common goal in the application of positive end-expiratory pressure (PEEP) is restoration of normal FRC All other things being equal, pleural pressure, which opposes thoracic recoil, should be the same at end-expiration whether breathing is spontaneous or mechanical Pleural pressure is, after all, determined by thoracic volume during passive expiration During spontaneous inspiration, active reshaping of the thorax by the respiratory muscles and diaphragm inflates the lungs by reducing pleural pressure In contrast, throughout positive pressure mechanical inspiration, pleural pressure rises because the passive thorax is pushed outward (from FRC to end-inspiratory volume) by the expanding lungs Passive expiration restores pleural pressure to that of FRC Averaged over the entire respiratory cycle, pleural pressure is higher during positive pressure breathing than it would be during spontaneous breathing (Fig 32.4) This elevation of pleural pressure during positive pressure mechanical ventilation may be thought of as transmission of airway pressure to the pleural space PPV, therefore, reverses the effects of spontaneous breathing on venous return12 and the RV diastolic Ptm.13 RV stroke volume declines during positive pressure inspiration as Pra rises and the effective compliance of the RV decreases Averaged over the entire respiratory cycle, Pra is raised and RV stroke volume is reduced by positive airway pressure relative to their expected values during spontaneous breathing It is easy to argue from these observations that PPV will invariably decrease venous return to the right heart, but this is not always the case In addition to the extent to which airway pressure is transmitted to the right heart, discussed further later, the ability of circulatory reflexes to maintain an adequate albeit elevated Pms, as well as underlying cardiac function, determines the extent to which stroke volume and CO is adversely impacted by PPV Venoconstriction and retention of intravascular volume act to elevate the Pms and maintain an adequate pressure gradient for systemic venous return During PPV, descent of the diaphragm may displace blood from the abdominal viscera14,15 and positive airway pressure may displace blood from the pulmonary circulation, both of which raise Pms Critical Illness and the Effects of Positive Pressure Breathing on RV Preload Among the effects of critical illness are inflammation-induced capillary leak, pulmonary edema, surfactant dysfunction, abnormal blood volume, and abdominal distension Each of these modifies the effects of positive pressure breathing on RV function and loading conditions Capillary leak alters the compliance of the atrial and ventricular chambers, modifying the responsiveness of the heart to changes in preload Sepsis and inflammation decrease cardiac contractility, directly altering the heart’s responses to changes in loading conditions Reduced lung compliance diminishes the transmission of alveolar pressure to the juxtacardiac space.16 The change in ITP that occurs with a change in static airway pressure is essentially the same as the change observed in pulmonary artery wedge pressure,17 which is readily measured Recognizing this relationship in adults has made it possible to estimate percent transmission of airway pressure to the juxtacardiac space by measurement of respiratory system compliance Lesions of the chest wall (consisting of the thoracic cage and diaphragm, the latter mechanically linking the abdominal cavity to the thorax) also impact compliance of the respiratory system and, in turn, alter pleural and juxtacardiac pressures and transpulmonary pressure.18 For a given airway pressure and lung compliance, as chest wall compliance decreases, the transpulmonary pressure (and lung volume) decreases, and the degree to which airway pressure is transmitted to and sensed by the heart increases.18 Lesions of the chest wall commonly seen in critical illness include pleural effusions, edema of the thoracic cage, ascites, and abdominal visceromegaly Respiration and Right Ventricular Afterload Respiration impacts RV afterload by modifying pulmonary vascular resistance (PVR) as a result of changes in lung volume and the distribution of blood flow within the lung, alveolar oxygen tension (PAO2), and carbon dioxide clearance/blood pH Because the ... Volume load Spontaneous breathing Positive pressure breathing Valsalva maneuver Pleural pressure SVrv (mL) Positive pressure ventilation Insp Exp Ppl at FRC Spontaneous breathing • Fig 32.4 Over... respiratory cycle, pleural pressure is higher during positive pressure breathing than it would be during spontaneous breathing (Fig 32.4) This elevation of pleural pressure during positive pressure mechanical... respiratory cycle.6–8 During spontaneous breathing, lung volume rises from FRC to end-inspiratory volume by expansion of the rib cage and descent of the diaphragm This reshaping of the thorax stretches