A comparison of inhaled nitric oxide and milrinone for the treatment of pulmonary hypertension in adult cardiac surgery patients

A Comparison of Inhaled Nitric Oxide and Milrinone for the Treatment of Pulmonary Hypertension in Adult Cardiac Surgery Patients Alann Solina, MD, Denes Papp, MD, Steven Ginsberg, MD, Tyrone Krause, MD, W i l l i a m Grubb, MD, Peter Scholz, MD, Leini-Luck Pena, MD, and Ronald Cody, EdD Objective: To investigate the relative effects of milrinone and nitric oxide on pulmonary and systemic hemodynamic responses in cardiac surgery patients with a history of pulmonary hypertension. Design: Prospective and randomized. Setting: University hospital. Participants: Forty-five adult cardiac surgery patients. Interventions: Cardiac surgery patients with pulmonary hypertension were randomly assigned to one of three study groups: Group 1 patients (n = 15) were treated with intravenous milrinone on separation from cardiopulmonary bypass, group 2 patients (n = 15) with 20 ppm of inhaled nitric oxide, and group 3 patients (n = 15) with 40 ppm of inhaled nitric oxide. Heart rate, right ventricular ejection fraction, and pulmonary vascular resistance were measured throughout the perioperative period at specific data points.

Measurements and Main Results: There were no significant differences in demographics, anesthesia, surgery, or baseline hemodynamics among the groups. The group receiving 40 ppm nitric oxide had a significantly higher (p < 0.05) right ventricular ejection fraction on arrival in the intensive care unit (40% v30% for the milrinone group and 33% for the nitric oxide 20 ppm group). The milrinone group required significantly more phenylephrine in the intensive care unit (p < 0.05). Conclusions: Treatment of pulmonary hypertension in adult cardiac surgery patients with inhaled nitric oxide compared with milrinone is associated with lower heart rates, higher right ventricular ejection fraction, and a lower requirement for treatment with vasopressor agents.

HE APPRECIATION of the importance of nitric oxide (NO) as a ubiquitous endogenous mediator of vascular tone has led to a plethora of scientific investigations that have sought to delineate the role of inhaled NO in treating pulmonary hypertension of various causes. Perhaps the least investigated role is the application of inhaled NO for therapy of adult cardiac surgery patients with pulmonary hypertension. During cardiac surgery, pulmonary hypertension and its deleterious effects on the right side of the heart may be aggravated by the release of vasoactive substances during cardiopulmonary bypass (CPB), 1 by a reduction of endogenous NO during CPB, 24 by the obligatory myocardial ischemia that is seen during CPB, or as a result of an unfavorable change in loading conditions that is sometimes imposed on the left ventricle as a consequence of valve replacement. In this scenario, inotropes, pulmonary vasodilators, or inotropes with pulmonary vasodilatory properties (inodilators) are frequently used to facilitate separation from CPB. In fact, it is a relatively common practice to employ inodilators empirically during separation from CPB in patients with a history of valve disease complicated by pulmonary hypertension with or without an element of right ventricular systolic dysfunction. These agents are all nonspecific vasodilators, and invariably result in a degree of systemic vasodilation that often necessitates therapeutic intervention with vasopressors. The therapeutic utility of inhaled NO derives from its specificity as a pulmonary vasodilator and its attendant beneficial effect on pulmonary ventilation/perfusion dynamics. The clinical administration of inhaled NO is relatively difficult,

however. The clinician must obtain an Investigational New Drug permit number from the U.S. Food and Drug Administration and must have access to a proper delivery system and monitoring equipment. Additionally, specially qualified personnel must continuously monitor the administration of inhaled NO. The administration of conventional agents in the perioperative setting is unequivocally less cumbersome. There is a relative paucity of studies that have examined the use of inhaled NO in the setting of adult cardiac surgery. 6-12 No studies have prospectively compared the therapeutic utility and effect on hemodynamic profile of inhaled NO therapy with that of more conventional agents. To determine whether the added expense and effort involved in the administration of inhaled NO are justified, the therapeutic utility of NO must be compared with that of conventional agents. The present study compares the relative effects of milrinone and inhaled NO on pulmonary and systemic hemodynamic responses in cardiac surgery patients with a history of pulmonary hypertension. The authors chose to compare NO with milrinone because this agent is commonly used in the treatment of pulmonary hypertension during cardiac surgery in adults.

T

From the UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ. Funded in part by a research grant from Sanofi, Inc. Address reprint requests to Alann Solina, MD, Department of Anesthesia, RWJMS, Suite 3100, CAB, 125 Paterson St, New Brunswick, NJ. Copyright © 2000 by W..B. Saunters Company 1053-0770/00/1401-0004510.00/0 12

Copyright © 2000 by W.B, Saunders Company KEY WORDS: pulmonary hypertension, cardiac surgery, nitric oxide

MATERIALS AND METHODS This prospective, randomized, but nonblinded study was approved by the Institutional Review Board of the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey. Subjects were 45 consecutive consenting adult cardiac surgery patients whose pulmonary vascular resistance (PVR) was greater than 125 dyne • sec - cm -5 immediately before induction of anesthesia (as calculated from measurements derived from the pulmonary artery catheter). Patients with a history of preoperative dependence on inotropes or vasopressors, patients with asthma, and pregnant patients were excluded from the study. Patients were premedicated with intramuscular morphine, 0.05 to 0.1 mg/kg, and intramuscular scopolamine, 0.004 to 0.006 mg/kg. Anesthesia was induced with a combination of midazolam, etomidate, fentanyl, and succinylcholine after preoxygenation with 100% oxygen. Anesthesia was maintained with fentanyl, isoflurane, midazolam, and rocuro-

Journal of Cardiothoracic and Vascular Anesthesia,

Vo114,No 1 (February),2000:pp 12-17

TREATMENT OF PULMONARY HYPERTENSION

nium. All patients were ventilated with 100% oxygen throughout the perioperative period. Each patient was monitored with an intra-arterial catheter for continuous blood pressure monitoring. A right ventricular ejection fraction (RVEF)-capable pulmonary artery catheter (Swau-Ganz Thermodilution Ejection Fraction/Volumetric Catheter, Baxter International, Santa Ana, CA) coupled to an RVEF/thermodilution cardiac output computer (REF-1, Baxter International) was used. This system provided continuous pulmonary artery pressure and central venous pressure monitoring, plus intermittent pulmonary capillary wedge pressure monitoring, thermodilution cardiac output determination, and RVEE determinations. Cardiac output and RVEF measurements were obtained as the mean of three end-expiration determinations made using injectares of 10 mL of normal saline at a temperature of 0°C. PVR and systemic vascular resistance (SVR) were calculated using standard formulae. The delivered concentration of inhaled NO and nitrogen dioxide was measured with electrochemical ceils (NOX BOX, Bedfont Medical, Kent, England). BOC Gases (Port Allen, LA) supplied NO as an 800 or 400 ppm mixture diluted in nitrogen. The NO/nitrogen mixture was pressure regulated, then blended with medical-grade nitrogen to achieve the desired final concentration. The final blended gas was then introduced to the fresh gas inlet of the anesthesia machine when delivering NO in the operating room, or via the low-pressure inlet of a Siemens Serve Ventilator, Model 900 D (Siemans-Elema AB, Solna, Sweden) when delivering NO in the intensive care unit (ICU). A sample of the final gas mixture was analyzed for NO, and nitrogen dioxide concentration analysis was done in a continuous fashion as described previously. A scavenging system was employed in the operating room and the ICU to reduce room pollution. CPB was accomplished using a Sarns 9000 CPB machine (Sarrls/3M, Ann Arbor, MI), with a Sarns Turbo membrane oxygenator (Sarns/3M). Nonpulsatile flow at a rate of 2.4 L/min/m2 was employed. The circuit was primed with 1,200 mL of Ringer's solution, 500 mL of hetastarch, 100 mL of 15% mannitol, and 50 mL of 25% albumin. The heart was arrested with cold, anterograde, hyperkalemic, blood cardioplegia that was not enhanced with amino acids. The patient was cooled to a venous return temperature of 28°C while on bypass and was rewarmed to a rectal temperature of 36°C before separation from CPB. Alpha-stat pH management was used while on CPB. Atrial pacing (rate 80 to 100 beats/min) was used for bradycardia (heart rate < 65 beats/min) before separation from CPB. Patients were assigned by random number allocation to the milrinone group or one of two NO groups preoperatively. Patients randomized to the milrinone group (n = 15) had milrinone initiated by bolus administration (50 gg/kg) 15 minutes before separation from CPB. Milrinone was maintained at 0.5 gg/kg/min in the operating room and for the first 24 hours in the ICU. Patients in the NO group were randomized to receive either 20 ppm (n = 15) or 40 ppm (n = 15) of medical-grade NO on termination of CPB (ie, restitution of pulmonary artery flow). NO administration was continued for the first 24 hours in the ICU. Table 1 summarizes the algorithm used to treat disturbances related to blood pressure, cardiac index, SVR, and PVR in the operating room and in the ICU. This algorithm was developed in conjunction with the Section of Cardiac Surgery at Robert Wood Johnson Medical School and is an amalgamation of standard clinical practice guidelines for cardiac surgery patients at the facility. Heart rate, arterial blood pressure, pulmonary artery pressures, pulmonary capillary wedge pressure, central venous pressure, cardiac output, cardiac index, SVR, PVR, and RVEF were recorded at the following times: preinduction, postinduction, after heparin dose, after CPB separation, after protamine, on chest closure, and before leaving the operating room, mad on arrival to the ICU. The average dose of inotropic and pressor agents used intraoperatively and postoperatively was recorded for each patient.

13

Table 1. Therapeutic Algorithm for Hemodynamic Disturbances Primary Hemodynamic Disturbance BP increased >25% over baseline BP

First-Line Therapy

Second-Line Therapy

Anesthesia/ sedation

Nitroglycerin

Third-Line Therapy

Nitroprusside

SVR > 1,200 (dyne. sec • cm -s) Nitroglycerin

Nitroprusside

Hypotension, SVR <800 (dyne • sec • cm s)

Phenylephrine Norepinephrine

PVR > initial, CI >2.0 (L/min/m 2) Nitroglycerin

Nitroprusside

CI <2.0 (Umin/m2), PVR > initial CI <2.0 (L/min/m2), PVR < initial

Dobutamine Epinephrine

Dopamine

Abbreviations: BP, blood pressure; SVR, systemic vascular resistance; CI, cardiac index,

Data were statistically analyzed using standard analysis of variance (ANOVA) in conjunction with Student-Newman Keuls multiple comparison tests. Wilcoxon rank sum analysis was used in cases in which ANOVA assumptions were not satisfied. All tests were two-sided. A two-way ANOVA (group by time) with time as a repeated measure factor was performed on the variables heart rate, mean arterial pressure, mean pulmonary artery paessure, cardiac index, PVR, SVR, and RVEF using the values from postbypass to arrival at the ICU. When either the group effect was significant (p < 0.05) or a significant interaction (group by time) was present, an analysis at each time point was performed. A p value <0.05 was considered significant. RESULTS

T h e three groups did n o t differ statistically with regard to d e m o g r a p h i c data or N e w York Heart A s s o c i a t i o n classification (Table 2). T h e three groups also did not differ statistically with respect to CPB, surgical, or a n e s t h e s i a t r e a t m e n t (Table 2). Baseline h e m o d y n a m i c p a r a m e t e r s did not differ in a statistiTable 2. Patient Characteristics Nitric Nitric Milrinone Oxide 20 Oxide 40 (n - 15) ( n - 15) (n - 15) Mean-+SD Mean+SD Mean-+SD pValue Demographics Age (yr) Weight (kg) Height(cm) NYHAclass

66-+12 70 -+ 15 161 -+ 14 3.5-+ 0.5

73_+11 73 _+ 19 164_+ 10 3.5 _+ 0.6

62_+15 71 -+ 18 162 _+ 19 3.1 ÷ 0.5

0.13 0.88 0.79 0.12

120 _+ 34 73 _+ 24 0.9-+1.1 0.3 -+ 0,5 1.1 -+ 0.7

120 _+ 44 67 -+ 31 1.1-+ 1.2 0.1 _+ 0.4 1.0 _+ 0.5

122 _+ 43 72 -+ 25 0.6-+0.7 0.1 -+ 0.3 1.0 _+ 0.5

0.98 0.77 0.38 0.32 0.94

2.8 ± 0.9

3.4 ± 1.1

3.5 -- 1.0

0.14

7.2 -+ 3.1

7.7 -+ 2.7

9.1 -+ 4.8

0.35

Cardiopulmonary bypass/anesthesia Bypass t i m e ( r a i n ) Cross-clamp time (rain) No. venous grafts No. arterial grafts No. valves replaced Total fentanyl dose (rag) Total midazolam dose (rag)

Abbreviations: SD, standard deviation; NYHA, N e w York Heart Association.

14

SOLINA ET AL

Table 3. Hemodynamic Data Baseline Mean -+ SD

Post Heparin Mean +- SD

Post CPB Mean +, SD

Chest Closure Mean + SD

End of Operation Mean -+ SD

[CU Arrival Mean +- SD

HR (beats/min) M

80 +_ 23

75 _+ 17

103 _+ 14

105 ± 17

103 + 17

109 ± 19

20

75 ± 18

83 _+ 19

92 _+ 9

99 _+ 21

100 ± 22

94 ± 18

40

84 ± 20

82 ± 19

94 ± 13

94 ± 13

96 ± 13

94 _+ 15

MAP (mmHg) M

101 _+22

76±9

79+17

81 ÷ 9

85+14

76±17

20

99 ± 18

84 ÷ 12

69 ± 11

77 ± 8

86 ± 15

90 _+ 13"

40

99 ± 15

79 ± 12

70 ± 11

78 ± 10

80 ± 10

85 _+ 13

MPAP ( m m H g ) M

39±9

26±9

23_+7

23_+5

24± 5

25±5

20

4 4 ± 11

37+17"

27±7

26+9

27+7

28±6

40

4 3 ± 13

30±8

26±4

28±7

28±7

26-+6 2.5 ± 0.7

CI (L/min) M

2.1 ± 0.5

2.2 ± 0.7

2.8 ± 0.5

2.6 ± 0.7

2.8 ± 0.7

20

2.3 -+ 1.0

2.1 _+ 0.7

2.6 ± 0.4

2.7 + 0.7

2.6 ± 0.5

2.5 ± 0.8

40

2.2 ± 0.8

2.0 ± 0.7

2.3 ± 0.8

2.7 -+ 0.7

2.6 ± 0.8

2.5 ± 0.7

PVR (dyne • sec. cm -5) M

336 ÷ 209

142 ± 84

142 ± 88

141 ± 79

163 ± 100

244 ± 127

20

435 ± 321

360 ± 316"

159 ÷ 124

147 ± 94

165 ± 99

235 ± 109

40

344 -+ 229

189 -+ 197

175 _+ 87

158 -+ 69

145 -+ 82

193 -+ 72

SVR (dyne • sec • cm -~) M

2074 ± 701

1494 -+ 581

1208 -+ 372

1346 ± 352

1308 + 413

1273 + 472

20

1787 ± 592

1504 ± 703

1080 ± 303

1125 ± 287

1289 ± 447

1585 ± 666

40

2014 ± 679

1938 ÷ 1217

1337 _+ 646

1237 ± 633

1304 ± 690

1330 ± 604

RVEF (%) M

26±12

31±12

37±7

35±10

35÷9

30÷9

20

27 ± 14

32 ± 11

35 ± 10

35 ± 11

36 ± 10

33 ÷ 10

40

31 ± 1 2

30 + 9

30÷11

39 + 9

41 _+7

40-+9"

Abbreviations: SD, standard deviation; CPB, c a r d i o p u l m o n a r y bypass; ICU, intensive care unit; M, milrinone; 20, nitric o x i d e 20 p p m ; 40, nitric o x i d e 40 ppm; HR, heart rate; MAP, mean arterial pressure; MPAP, mean p u l m o n a r y artery pressure; CI, cardiac index; PVR, p u l m o n a r y vascular resistance; SVR, systemic vascular resistance; RVEF, right ventricuiar ejection fraction. *Denotes g r o u p significantly different (p < 0.05).

450

400

350

E 300 o

n ~ 250 t->, -o

2O0

150

100

Nitric or Mdrinone Started

I

Baseline

~

~

I

I

P-heparin

P-CPB

Time

I

I

C l o s u r e E n d of C a s e

I

ICU

Fig 1. Pulmonary vascular resistance (PVR) as a function of time. *p < 0.05. Abbreviations: Baseline, preinduction; P-heparin, postheparin; P-CPB, postbypass; Closure, chest closure; End of Case, immediately before transport to the intensive care unit (ICU); ICU, on ICU arrival. O, milrinone; ©, NO 20; T, NO 40.

TREATMENT OF PULMONARY HYPERTENSION

15

120

110

~-1oo n~

Tmv 9O

~

Fig 2. Heart rate as a function of time. *p < 0.05. Abbreviations: Baseline, preinduction; Pheparin, postheparin; P-CPB, postbypass; Closure, chest closure; End of Case, immediately before transport to the intensive care unit (ICU); ICU, on ICU arrival. 0, milrinone; ©, NO 20; 'I', NO 40.

N

~~xJde

80

one

d

70

I

I

I

I

I

I

Baseline

P-Heparin

P-CPB

Closure

End of Case

ICU

Time

cally significant fashion (Table 3). Specifically, the baseline PVR, cardiac indices, and RVEF did not differ among the three groups (Table 3). After administration of anesthesia (postheparin data point), the mean pulmonary arterial pressure (MPAP) and PVR (Fig 1) were statistically higher in the NO 20 group (Table 3). After initiation of the therapeutic regimen (NO or milrinone), there were no differences in PVR among the three groups at any data point (Fig 1). There were also no significant differences among

~,

groups for cardiac index or SVR at any time (Table 3). At all data points after the initiation of the therapeutic regimen (ie, postbypass), the group receiving milrinone tended to have a higher heart rate (Fig 2), although this did not reach statistical significance (p = 0.11). On arrival in the ICU, the NO 20 group had a statistically higher mean arterial pressure than the other two groups (Table 3). The NO 40 group had a statistically higher RVEF on arrival in the ICU than either of the other two groups (Fig 3).

42 40 38 36 34 LLI

32 30 28

o//

or Milrinone Started

26

,I,

24 Baseline

P- heparin

P-CPB

Time

Closure End of Case

ICU

Fig 3. Ejection fraction as a function of time. *p < 0.05. Abbreviations: Baseline, preinduction; P-heparin, postheparin; PCPB, postbypass; Closure, chest closure; End of Case, immediately before transport to the intensive care unit (ICU), ICU, on ICU arrival. O, milrinone; O, NO 20; , , NO 40.

16

SOLINA ET AL Table 4. Average Dose of Inotropes/Pressors Used Postbypass and in the ICU (tLg/kg/min) Postbypass pValue Mean ± SD Dobutamine

ICU (First 24 hr) p Value Mean -+ SD

p = 0.28

p = 0.23

M

0.1 ± 0,56

0.7 -+ 1.69

20

0.6 + 1.65

2.4 -+ 3.12

40

0.0 -+ 0.00

3.1 .+ 2.80

Dopamine

p = 0.71

p = 0.33

M

0.1 + 0.5

0.5 ± 0.67

20

0.5 .+ 1.81

0.4 ± 0,67

40

0.3 ÷ 0.70

0.8 -+ 0.88

Epinephrine M

p = 0.04

p = 0.84

0.0 .+ 0.05

0.0 -+ 0.11

20

0.1 .+ 0.14

0.0 -+ 0.05

40

0.0 -+ 0.04

0.0 ± 0.03

Milrinone

p = 0.0001

p = 0,001

M

0.5 -- 0.09*

0.4 ± 0.20*

20

0.0 ± 0.00

0.0 .+ 0.00

40

0.0 -+ 0.00

0.0 -+ O.00

Nitroglycerin

p = 0.82

p = 0.09

M

0.0 ± 0.19

0.2 + 0.55

20

0.0 .+ 0.07

0.5 -+ 0.50

40

0.1 _+ 0.21

0.7 .+ 0.79

Nitroprusside

p = 0.37

p = 0.26

0.0 -+ 0.00

0.0 ± 0.00

20

0.1 -+ 0.31

0.1 _+ 0.31

40

0.0 -+ 0.00

0.0 -- 0.00

M

Norepinephrine

p = 0.10

p = 0.53

M

0.1 ± 0.20

0.2 .+ 0.50

20

0.0 + 0.03

0.0 _+ 0.03

40

0.0 _+ 0.00

0.2 ± 0.72

Phenylephrine

p = 0,49

p = 0.01

M

0.1 _+ 0.14

0.3 + 0.72*

20

0.1 ± 0.24

0.1 ± 0.16

40

0.0 ± 0.08

0.1 ± 0.10

Abbreviations: ICU, intensive care unit; SD, standard deviation; M, milrinone; 20, nitric oxide 20 ppm; 40, nitric oxide 40 ppm. *Denotes group significantly different (p < 0.05).

ANOVA revealed a significant difference in epinephrine used across the groups in the post-CPB period; however, StudentNewman Keuls multiple comparison test failed to reveal heterogeneity across groups (Table 4). The milrinone group required significantly more phenylephrine than either of the NO groups in the ICU (Table 4). DISCUSSION

The role of NO as a specific pulmonary vasodilator in the setting of adult cardiac surgery is well established. Previous studies, however, have not prospectively compared the treatment of pulmonary hypertension with inhaled NO versus conventional inodilators. The present study sought to determine the differential effect that the two therapies have on hemodynamic parameters and consequent requirement for the use of inotropic and pressor agents. Although no significant differences in demographic data or baseline hemodynamic data were found among groups, the sample size was relatively small, and it is possible that there was unappreciated heterogeneity among the groups in this regard.

The study design limited the development of a significant disparity in many critical hemodynamic parameters because it was considered unethical not to treat patients with significant disturbances in hemodynamic profile so that investigators could document the disparity. A hemodynamic profile goal and a therapeutic algorithm to keep patients within the confines of this goal were established. The disparity in the amount of vasoactive drug required by this algorithm is presumably a reflection of the difference in hemodynamic effect associated with the treatment modality. This study suggests that adult cardiac surgery patients with a history of pulmonary hypertension who are treated with inhaled NO require less vasopressor agent support postoperatively than patients treated with milrinone (average dose of phenylephrine in the ICU was 0.3 + 0.7 gg/kg/min for patients in the milrinone group v 0.1 -+ 0.1 gg/kg/min for each of the NO groups; p = 0.01). The requirement of pressor agent support is an indication of hemodynamic instability. Additionally, morbidity is associated with the use of pressor agents in terms of compromised organ perfusion, arrhythmias, and pulmonary vasoconstriction. There was no significant disparity in the cardiac indices of patients treated with milrinone versus inhaled NO (Fig 4). It might intuitively have been anticipated that the patients in the milrinone group would have a greater cardiac index and possibly RVEF on the basis of milrinone being a positive inotrope, whereas inhaled NO has no known direct inotropic effect. That inhaled NO patients did not require significantly greater inotropic support than milrinone patients may argue that simply unloading the right ventricle allowed it to enjoy enough of a mechanical advantage to obviate the necessity for treatment with an inotropic agent. The greater requirement and use of phenylephrine in the ICU by milrinone patients would be expected to produce a deleterious effect on PVR and consequently RVEE Despite having the lowest initial PVR, the milrinone group had the highest PVR in the ICU. This disparity did not achieve statistical significance but may partially explain why patients receiving 40 ppm of NO had a significantly higher RVEF than the patients treated with milrinone on arrival in the ICU. The relatively short half-life of inhaled NO does not necessarily preclude a direct or indirect inotropic effect on myocardial tissue. This issue warrants further scientific evaluation. The group of patients receiving NO at 20 ppm had a significantly higher mean arterial pressure on arrival in the ICU than patients in either of the other two groups. Milrinone patients tended to have higher heart rates after CPB when compared with either NO group (although this difference did not reach statistical significance). It is unclear whether the lower mean arterial pressure engendered a reflexive tachycardia in the milrinone group or if the tachycardia was a consequence of milrinone's positive chronotropic effect. Additionally, it is possible that there were differences in anesthetic depth or preoperative use of sympathetic blocking agents among groups that may have engendered the heart effect that was observed in this study.

TREATMENT OF PULMONARY HYPERTENSION

17

3.0

2.8

2.6

X "Z3

¢

E 0

Fig 4. Cardiac index as a function of time. Abbreviations: Baseline, preinduction; P-heparin, postheparin; P-CPB, postbypass; Closure, chest closure; End of Case, immediately before transport to the intensive care unit (ICU); ICU, on |CU arrival. @, milrinone; O, NO 20; , , NO 40.

2.2 Oxide

"~

2.0

or Milrinone Started

I 1.8

I

I

Baseline

P-heparin

~1

I

P-CPB

I

Closure End of Case

I

ICU

Time

In conclusion, the present study demonstrated that the treatment of pulmonary hypertension in adult cardiac surgery patients with inhaled NO is associated with a favorable effect on RVEF and a reduced requirement for treatment with pressor

agents when compared with treatment with milrinone. Further studies are needed to elucidate the effect the use of inhaled NO has on the morbidity and mortality of adult cardiac surgery patients.

REFERENCES

1. Erez E, Erman A, Snir E, et al: Thromboxane production in human lung during cardiopulmonary bypass: beneficial effect of aspirin? Ann Thorac Surg 65:101-106, 1998 2. Morita K, lhnken K, Buckberg GD, et al: Pulmonary vasoconstriction due to impaired nitric oxide production after cardiopulmonary bypass. Ann Thorac Surg 61:1775-1780, 1996 3. Seghaye MC, Dnchateau J, Bruniaux J, et al: Endogenous nitric oxide production and atrial natriuretic peptide biological activity in infants undergoing cardiac operations. Crit Care Med 25:1063-1070, 1997 4. Kirshbom PM, Jacobs MT, Tsni SS, et al: Effects of cardiopulmonary bypass and circulatory arrest on endothelium-dependent vasodilation in the lung. J Thorac Cardiovasc Surg 111:1248-1256, 1996 5. Duke T, South M, Stewart A: Altered activation of the L-arginine nitric oxide pathway during and after cardiopulmonary bypass. Perfusion 12:405-410, 1997 6. Rich GF, Murphy GD Jr, Roos CM, Johns RA: Inhaled nitric oxide: selective pulmonary vasodilation in cardiac surgical patients. Anesthesiology 78:1028-1035, 1993

7. Bacha EA, Head CA: Use of inhaled nitric oxide for lung transplantation and cardiac surgery. Respir Care Clin North Am 3:521-536, 1997 8. Fullerton DA, McIntyre RC Jr: Inhaled nitric oxide: therapeutic applications in cardiothoracic surgery. Ann Thorac Surg 61:1856-1864, 1996 9. Snow DJ, Gray SJ, Ghosb S, et al: Inhaled nitric oxide in patients with normal and increased pulmonary vascular resistance after cardiac surgery. Br J Anaesth 72:185-189, 1994 10. Fullerton DA, Jaggers J, Piedalue F, et al: Effective control of refractory pulmonary hypertension after cardiac operations. J Thorac Cardiovasc Snrg 113:363-368, 1997 11. Fullerton DA, Jones SD, Jaggers J, et al: Effective control of pulmonary vascular resistance with inhaled nitric oxide after cardiac operation. J Thorac Cardiovasc Surg 111:753-762, 1996 12. Lindberg L, Larsson A, Steen S, et al: Nitric oxide gives maximal response after coronary artery bypass surgery. J Cardiothorac Vasc Anesth 8:182-187, 1994