SEARCH

SEARCH BY CITATION

Keywords:

  • Blood pressure: pulmonary; hypertension;
  • Drug: phenylephrine; norepinephrine

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. References

In this study the effect of phenylephrine and norepinephrine for the treatment of systemic hypotension were evaluated in patients with chronic pulmonary hypertension. When systemic hypotension (systolic arterial pressure < 100 mmHg) occurred following induction of anaesthesia, either phenylephrine or norepinephrine were infused in a random manner to raise the systolic blood pressure by 30% and 50% above baseline values. Norepinephrine decreased the ratio of pulmonary arterial pressure to systemic blood pressure without a change in cardiac index. However, phenylephrine did not increase arterial blood pressure by more than 30% from baseline in one-third of patients and decreased cardiac index without a significant decrease in ratio of pulmonary arterial pressure to systemic blood pressure. These vasoconstrictors showed different systemic and pulmonary haemodynamic effects in patients with chronic pulmonary hypertension as compared to acute pulmonary hypertension. Norepinephrine was considered to be preferable to phenylephrine for the treatment of hypotension in patients with chronic pulmonary hypertension.

Pulmonary hypertension may result from a number of different conditions producing a chronic increase in pulmonary arterial pressure (PAP). Generally, PAP > 35 mmHg systolic and 15 mmHg diastolic pressure or a mean pressure > 20 mmHg at rest or 30 mmHg with exercise is indicative of pulmonary hypertension [1]. In the vast majority of patients, pulmonary hypertension is secondary to cardiac or pulmonary disease [2].

The clinical significance of pulmonary hypertension lies in the resultant right ventricular failure and consequent left ventricular failure [3]. Right ventricular performance is governed by preload, afterload, contractility and heart rate. In contrast to the left ventricle, small increases in right ventricular afterload are associated with a sharp decrease in right ventricular ejection fraction [4]. The therapy and prevention of right ventricular failure caused by pulmonary arterial hypertension requires the combination of vasodilators producing a decrease in pulmonary vascular resistance (PVR) and a peripheral vasoconstrictor to produce an increase in coronary blood flow [5].

Most patients with chronic pulmonary hypertension undergoing mitral valvular surgery are hypovolaemic when they arrive in the operating theatre due to long-term diuretic therapy. Systemic hypotension frequently occurs following induction of anaesthesia. Systemic hypotension should be treated vigorously in these patients, the ideal drug being one which increases the systemic arterial blood pressure (SBP) but producing minimal effects on pulmonary arterial pressure. A number of studies in animal models or in patients with acute pulmonary hypertension have reported that phenylephrine or norepinephrine effectively increased SBP with an increase in cardiac output and concomitantly decreased PAP and pulmonary vascular resistance index [6–11]. However, little is known about the effects of these vasoconstrictors in patients with chronic pulmonary hypertension undergoing open heart surgery. The pathophysiology of the right ventricle and pulmonary vasculature may be different from patients with acute pulmonary hypertension.

This study was designed to investigate the pulmonary and systemic effects of phenylephrine and norepinephrine in patients with chronic pulmonary hypertension undergoing open heart surgery.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. References

Following Institutional Board of Clinical Research approval, 27 patients undergoing valvular heart surgery or repair of congenital heart defects whose mean pulmonary arterial pressures were known to be > 25 mmHg were consented to participate in this study. The patients were randomly allocated into the phenylephrine or norepinephrine group.

Patients were premedicated with an intramuscular injection of morphine 0.1 mg.kg−1. On arrival in the operating room, electrocardiogram leads were attached and leads II and V5 were continuously monitored. A 20-gauge radial artery catheter was inserted to allow the continuous measurement of arterial blood pressure. A flow-directed pulmonary artery catheter was inserted into the pulmonary circulation via the right internal jugular vein. This catheter was used for measuring right atrial pressure (RAP), PAP and pulmonary capillary wedge pressure (PCWP). Cardiac output was measured in triplicate using the thermodilution technique; values of ± 10% of mean values were discarded.

Anaesthesia was induced using midazolam 2–3 mg, fentanyl 15–30 µg.kg−1 and maintained with fentanyl and 0.2–0.6% of isoflurane with oxygen and air at an inspired oxygen fraction of 60%. The trachea was intubated and pancuronium or vecuronium bromide (0.1–0.15 mg.kg−1) administered to produce neuromuscular blockade; ventilation was controlled using a non-rebreathing system. Tidal volume and respiratory rates were adjusted to maintain an arterial blood carbon dioxide tension of 30–35 mmHg.

If arterial systolic pressure decreased to < 100 mmHg and the mean PAP was > 25 mmHg following induction of anaesthesia, either phenylephrine (40 µg.ml−1) or norepinephrine (8 µg.ml−1) was administered according to the randomisation procedure at 50 ml.h−1 to raise the systolic arterial pressure up to 30% from baseline values. The drug infusion was temporarily stopped to allow the measurement of cardiac output and for the recording of haemodynamic parameters. After these measurements had been recorded, the drug infusion was restarted again to raise the systolic arterial pressure to 50% above baseline values.

Infusion of the drugs was stopped if (1) the systolic arterial pressure had increased to > 50% above baseline values; (2) the systolic arterial pressure had not changed significantly 3 min following the start of the infusion (100 µg phenylephrine or 20 µg norepinephrine); (3) a reflex bradycardia or arrhythmia appeared.

All patients were studied prior to skin incision to minimise the effect of surgical stimulation. The investigators were blind to which drug had been infused.

Haemodynamic parameters, including heart rate, SBP, RAP, PAP, PCWP and cardiac output, were measured at three time points: (1) before the infusion of phenylephrine or norepinephrine (T1); (2) when the systolic arterial pressure had increased up to 30% over baseline values (T2); (3) when systolic arterial pressure had increased up to 50% over the baseline values (T3).

Systemic vascular resistance index (SVRI) and pulmonary vascular resistance index (PVRI) were calculated using standard formulae. The ratio of mean PAP to mean SBP and the ratio of PVRI to SVRI were also calculated.

Summary statistics were expressed as means and standard deviations (SD). The effect of phenylephrine or norepinephrine infusion (comparison between T1 and T2, T3) was assessed by using a paired t-test and the comparison between the norepinephrine and phenylephrine groups was performed using an unpaired t-test. Statistical significance was defined as p < 0.05.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. References

There were no statistically significant differences between the two groups in terms of age, sex, body surface area and surgical procedures (Table 1).

Table 1.   Demographic data. Values are given as mean (SD).
 Phenylephrine (n = 14)Norepinephrine (n = 10)
  1. There were no significant differences between groups. BSA: body surface area, AVR: aortic valve replacement and mitral valve replacement, MVR: mitral valve replacement, ASD: atrial septal defect, VSD: ventricular septal defect.

Male: female ratio3/113/7
Age; years46.8 (12.1)41.4 (10.3)
BSA; m21.5 (0.2)1.6 (0.1)
Count of procedures
 AVR11
 MVR118
 ASD repair11
 VSD repair10

Twenty-seven patients were enrolled into this study; three patients were excluded from analysis, in two patients the systolic arterial pressure did not change following the infusion of phenylephrine for 3 min, and one patient developed a reflex bradycardia (heart rate < 40 beat.min−1) during the infusion of norepinephrine without any increase of systolic arterial pressure. Fourteen and 10 patients were allocated to the phenylephrine and norepinephrine groups, respectively. Systolic arterial pressure was increased to > 30% above baseline values in all patients in the phenylephrine group but could not be raised to > 50% above baseline values from T2 within 3 min in six patients in the phenylephrine group and the phenylephrine infusion was stopped. Therefore, the results of eight patients in the phenylephrine group were evaluated at T3.

However, in the norepinephrine group, systolic arterial blood pressure was successfully increased to > 50% above baseline values in all patients.

When the systolic arterial pressure was increased to > 30% over baseline values, heart rate significantly decreased in the phenylephrine group (p = 0.027) but not in the norepinephrine group and the cardiac index (CI) did not change significantly in either group. SVRI significantly increased in the phenylephrine group (p < 0.001). Mean PAP significantly increased in both groups (p = 0.001 in both groups). RAP and PVRI increased significantly only in the phenylephrine group (p = 0.004 and p = 0.046, respectively).

When the systolic arterial pressure was increased to > 50% above baseline values, the heart rate did not change in either group. However, the CI decreased significantly in the phenylephrine group (p = 0.008). SVRI significantly increased in both groups (p < 0.001 in the phenylephrine group and p = 0.008 in the norepinephrine group). Mean PAP (p < 0.001 in both groups), RAP (p < 0.001 in the phenylephrine group and p = 0.001 in the norepinephrine group) and PVRI (p = 0.027 in the phenylephrine group and p = 0.037 in the norepinephrine group) also significantly increased in both groups (Tables 2 and 3).

Table 2.  Effects of phenylephrine and norepinephrine on systemic circulation. Values are given as mean (SD).
 PhenylephrineNorepinephrine
T1T2T3T1T2T3
  1. T1: baseline, T2: when systolic blood pressure was raised up to 30% over the baseline, T3: when systolic blood pressure was raised up to 50% over the baseline, SBP: systolic blood pressure, HR: heart rate, CI: cardiac index, SI: stroke volume index, SVRI: systemic vascular resistance index. *p < 0.05, **p < 0.01, ***p < 0.001 (compared with control value).

SBP; mmHg95.3130.4148.291.0131.9152.0
(6.7)(1.8)***(4.2)***(11.8)(4.0)***(3.2)***
HR; beat.min−175.070.268.983.175.475.7
(15.4)(14.9)*(14.6)(22.5)(28.1)(22.7)
CI; 1.min−1.m−22.82.32.32.42.42.7
(1.3)(0.8)(0.6)**(0.6)(1.0)(1.0)
SI; ml.beat−1.m−239.435.234.231.133.236.6
(18.2)(15.5)(11.3)(10.4)(7.5)(16.3)
SVRI; dyne.s.cm−5.m−21901.73103.23487.12173.13431.93353.6
(562.8)(904.7)***(975.2)***(649.0)(2179.3)(1444.7)**
Table 3.   Effect of phenylephrine and norepinephrine on pulmonary circulation. Values are given as mean (SD).
 PhenylephrineNorepinephrine
T1T2T3T1T2T3
  1. T1: baseline, T2: when systolic blood pressure was raised up to 30% over the baseline, T3: when systolic blood pressure was raised up to 50% over the baseline, mPAP: mean pulmonary arterial pressure, RAP: right atrial pressure, PVRI: pulmonary vascular resistance index.*p < 0.05, **p < 0.01, ***p < 0.001 (compared with control value).

mPAP; mmHg31.340.442.331.437.341.3
(6.3)(10.4)**(10.2)**(5.3)(7.0)**(7.8)***
RAP; mmHg7.79.611.310.011.112.8
(3.2)(3.2)**(4.0)***(2.9)(3.4)(3.5)*
PVRI; dyne. s.cm−5.m−2313.4500.7491.7257.8340.9442.0
(121.5)(235.0)*(320.4)*(84.4)(78.4)(228.3)*

The ratio of mean PAP to mean SBP was reduced significantly in the norepinephrine group (p = 0.019), but not in the phenylephrine group when systolic arterial pressure was increased to 30% above baseline values. The ratio of PVRI to SVRI was not significantly changed in both groups. The ratio of mean PAP to mean SBP and the ratio of PVRI to SVRI did not show any statistical significance in both groups when the systolic arterial pressure was increased to 50% above baseline values (Table 4).

Table 4.   Changes in the relationship between systemic and pulmonary blood pressure and vascular resistance. Values are given as mean (SD).
 PhenylephrineNorepinephrine
 T1T2T3T1T2T3
  1. T1: baseline, T2: when systolic arterial pressure was raised up to 30% over the baseline, T3: when systolic arterial pressure was raised up to 50% over the baseline, RBP: the ratio of mean pulmonary arterial pressure to mean systemic blood pressure, RVRI: the ratio of pulmonary vascular resistance index to systemic vascular resistance index. *p < 0.05 (compared with control value).

RBP; %46.0 (9.3)43.2 (10.8)40.7 (10.1)44.2 (5.3)38.1 (9.9)*37.7 (8.6)
RVRI; %17.4 (7.8)18.6 (15.3)14.0 (7.8)12.4 (4.8)11.7 (5.9)13.3 (4.3)

There were no significant differences in haemodynamic measurements between the phenylephrine and norepinephrine groups at T1–T3(Tables 2–4).

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. References

In this study, neither norepinephrine nor phenylephrine demonstrated significant improvements in haemodynamic parameters in patients with chronic pulmonary hypertension, in contrast to patients with acute pulmonary hypertension.

Norepinephrine increased systolic arterial pressure successfully in all patients and decreased the ratio of mean PAP to mean systemic blood pressure, but did not show any positive effect on CI and PVRI. Phenylephrine did not increase systolic arterial pressure to > 30% above the baseline values in one-third of patients, and decreased heart rate and increased RAP and PVRI.

There have been a number of reports advocating the use of a vasoconstrictor to increase coronary perfusion pressure. This has been particularly emphasised in the management of patients with acute pulmonary hypertension accompanied by right ventricular failure. In clinical and animal studies of acute pulmonary hypertension, PAP and PVR decreased when SBP was raised with norepinephrine because subsequent increase in coronary perfusion pressure improved right ventricular function and increased cardiac output [12–15], although the effect of phenylephrine is debatable [6, 16]. Hirsch et al. [7] compared the effect of phenylephrine and norepinephrine in dogs with acute right ventricular failure induced by pulmonary embolism and found that only norepinephrine reduced PVR and increased coronary blood flow of the right ventricle and consequently improved right ventricular function and systemic haemodynamics.

From our results, it is clear that there are differences between patients with chronic and acute pulmonary hypertension in their response to vasoconstrictors. These differences seem likely to be attributable to the relatively well preserved right ventricular function and reduced preload in patients with chronic pulmonary hypertension. Although this study was not specifically designed to provide explanations for differences between the clinical situation in patients with chronic pulmonary hypertension and acute pulmonary hypertension produced in an animal model, it is likely that in the chronic situation the right ventricle undergoes muscular development during the gradual increase of right ventricle afterload. Right ventricle hypertrophy compensates for the increase of right ventricle wall tension and hence the systolic right ventricle function is preserved in chronic pulmonary hypertension. In most acute pulmonary hypertension models, cardiac output is very low and right ventricle function is markedly impaired. The action of norepinephrine on β-adrenergic receptors and coronary perfusion pressure produced a large change [6, 13, 15]. Angle et al. [13] and Ghignone et al. [15] proposed that norepinephrine might act on β-adrenergic receptors and increase right ventricle contractile function and cardiac output resulting in the decrease in PVR in the acute pulmonary hypertension model.

Our study was primarily designed to compare the ability of these two drugs (phenylephrine and norepinephrine) to treat hypotension, without producing significant increases in PAP, in patients with chronic pulmonary hypertension undergoing cardiac surgery.

Therefore, we did not include an evaluation of the right ventricle function in these patients. However, baseline CI was within normal limits, in contrast to the acute pulmonary hypertension model where CI was markedly reduced. In addition, patients with chronic pulmonary hypertension undergoing cardiac surgery were relatively hypovolaemic as a result of chronic diuretic therapy and fluid restriction. The low stroke volume index and high SVRI in the patients in our study, may have limited the increase of cardiac output in both groups and the increase of systolic arterial pressure in some of the patients in the phenylephrine group. An improvement of cardiac output recruits pulmonary circulation and decreases PAP and PVRI in acute pulmonary hypertension. Vasoconstriction of pulmonary vasculature without an increase in CI by vasoconstrictor might cause a concomitant increase of PAP and PVRI in this study.

There are some limitations to this study. Firstly, the study was designed simply to compare the ability of the two drugs, phenylephrine with norepinephrine, to raise systolic arterial pressure and to measure the effects on the other haemodynamic variables. It was not designed to measure right ventricle function. Second, preload was not precisely determined and controlled; variation in preload makes it difficult to compare our results with those of the acute pulmonary hypertension model. Hypovolaemia seemed to be an important cause of hypotension in our patients and may have limited the increase of stroke volume during administration of vasoconstrictors. It is possible that hypotension would have occurred less frequently if adequate hydration had been achieved pre-operatively or during the induction of anaesthesia. However, pre-operative hypovolaemia is commonly encountered in clinical practice, in patients with valvular heart disease.

Third, it is not known what level of SBP increases coronary perfusion pressure without producing significant increases in left ventricle wall tension and left ventricle afterload. It is not clear whether different results would have been observed if the norepinephrine or phenylephrine infusion were started at lower systolic arterial pressure, and whether the increase in the systolic arterial pressure at T2 and T3 caused a negative effect on the left ventricle by increasing the afterload in this study.

In conclusion, we found that norepinephrine increased SBP to a greater extent, causing less increase in PAP compared to phenylephrine; we therefore conclude that norepinephrine is considered preferable to phenylephrine for the treatment of hypotension in patients with chronic pulmonary hypertension.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. References
  • 1
    Fedullo PF, Auger WR, Channick RN. Pulmonary hypertension. In: BrownDL, ed. Cardiac Intensive Care. Philadelphia: W.B. Saunders Co., 1998: 493504.
  • 2
    Oliver WC, De Castro MA, Strickland RA. Uncommon diseases and cardiac anesthesia. In: KaplanJA, KonstadtSN, ReichDL, eds. Cardiac Anesthesia, 4th edn. Philadelphia: W.B. Saunders Co., 1999: 9257.
  • 3
    Laver MB, Strauss WH, Pohost GM. Herbert Shubin memorial lecture-right and left ventricular geometry: adjustments during acute respiratory failure. Critical Care Medicine 1975; 7: 50919.
  • 4
    Hess W. Effects of amrinone on the right side of the heart. Journal of Cardiovascular and Thoracic Anesthesia 1989; 3: 3844.
  • 5
    Cross CE. Right ventricular pressure and coronary flow. American Journal of Physiology 1962; 202: 1216.
  • 6
    Vlahakes GJ, Turley K, Hoffman JIE. The pathophysiology of failure in acute right ventricular hypertension: hemodynamic and biochemical correlations. Circulation 1981; 63: 8795.
  • 7
    Hirsch LJ, Rooney MW, Wat SS, Kleinmann B, Mathru M. Norepinephrine and phenylephrine effects on right ventricular function in experimental canine pulmonary embolism. Chest 1991; 100: 796801.
  • 8
    Mathru M, Venus B, Smith RA, Shirakawa Y, Sugiura A. Treatment of low cardiac output complicating acute pulmonary hypertension in normovolemic goats. Critical Care Medicine 1986; 14: 1204.
  • 9
    Ducas J, Duval D, Dasilva H, Boiteau P, Prewitt RM. Treatment of canine pulmonary hypertension: effects of norepinephrine and isoproterenol on pulmonary vascular pressure-flow characteristics. Circulation 1987; 75: 23542.
  • 10
    Calvin JE. Acute right heart failure: pathophysiology, recognition, and pharmacological management. Journal of Cardiothoracic and Vascular Anesthesia 1991; 5: 50713.
  • 11
    Molloy WD, Lee KY, Girling L, Schick U, Prewitt RM. Treatment of shock in a canine model of pulmonary embolism. American Review of Respir Disease 1984; 130: 8704.
  • 12
    Vincent JL, Carlier E, Pinsky MR, et al. Prostaglandin E1 infusion for right ventricular failure after cardiac transplantation. Journal of Thoracic and Cardiovascular Surgery 1992; 103: 339.
  • 13
    Angle MR, Molloy DW, Penner B, Jones D, Prewitt RM. The cardiopulmonary and renal hemodynamic effects of norepinephrine in canine pulmonary embolism. Chest 1989; 95: 13337.
  • 14
    D'Ambra MN, LaRaia PJ, Philbin DM, Watkins WD, Hilgenberg AD, Buckley MJ. Prostaglandin E1. A new therapy for refractory right heart failure and pulmonary hypertension after mitral valve replacement. Journal of Thoracic and Cardiovascular Surgery 1985; 89: 56772.
  • 15
    Ghignone M, Girling L, Prewitt RM. Volume expansion versus norepinephrine in treatment of a low cardiac output complicating an acute increase in right ventricular afterload in dogs. Anesthesiology 1984; 60: 1325.
  • 16
    Rich S, Gubin S, Hart K. The effects of phenylephrine on right ventricular performance in patients with pulmonary hypertension. Chest 1990; 98: 11026.