Ann Thorac Surg 1996;62:1677-1684
© 1996 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Pulmonary Arterial Endothelial Dysfunction Potentiates Hypercapnic Vasoconstriction and Alters the Response to Inhaled Nitric Oxide
Jeff L. Myers, MD, PhD,
Joseph J. Wizorek, BS,
Adam K. Myers, PhD,
Ekua Yankah,
Maria T. Pettit, BS,
Peter C. Kouretas, MD,
Heidi J. Dalton, MD,
Yining Wang, MD,
Richard A. Hopkins, MD
Departments of Surgery, Physiology and Biophysics, and Pediatrics, Georgetown University Medical Center, Washington, DC
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Abstract
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Background. Pulmonary hypertensive crisis can be initiated by episodes of hypercapnic acidosis. Hypercapnic vasoconstriction in the newborn pulmonary arterial circulation may be modulated by endogenous production of nitric oxide (NO) by the endothelial cell and effectively treated with inhalation of NO.
Methods. Sixteen 48-hour-old piglets were randomized to receive a hypercapnic challenge after administration of either saline vehicle or the NO synthase inhibitor N-
-nitro-L-arginine (L-NA). Pulmonary arterial pressure, flow, and radius measurements were taken at baseline, after infusion of vehicle or L-NA, during hypercapnia (inspired fraction of carbon dioxide, 0.15), and during inhalation of NO (100 ppm). Fourier analysis was used to calculate input mean impedance, reflecting distal arteriolar vasoconstriction, and characteristic impedance, reflecting proximal arterial geometry and distensibility.
Results. Input mean impedance was increased with L-NA administration. Animals pretreated with L-NA also underwent a much larger increase in input mean impedance with exposure to hypercapnia than untreated animals. Characteristic impedance increased in the treated animals, but not in the controls.
Conclusions. In the newborn pulmonary arterial circulation, endogenous NO production by the endothelial cell modulates resting tone distally, but not proximally. In addition, lack of a functional endothelium markedly potentiates the distal vasoconstrictor response to hypercapnia and produces proximal vasoconstriction. Despite impaired endothelial function, inhaled NO remains an effective vasodilator in hypercapnic pulmonary vasoconstriction.
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Introduction
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Nitric oxide derived from the vascular endothelium plays a critical role in the maintenance of pulmonary arterial and systemic hemodynamics [1]. Additionally, endothelial dysfunction and the loss of nitric oxide's vasodilatory effect may lead to an altered response to stressors such as hypoxia or hypercapnia [2, 3]. Both of these problems are encountered frequently in the postoperative management of children with congenital cardiac malformations. Additionally, inhaled nitric oxide has proved to be a selective pulmonary arterial vasodilator in both animal and human studies [4, 5]. The combination of these factors has resulted in tremendous interest in the modulation of pulmonary arterial hemodynamics by endogenous and exogenous nitric oxide.
The neonatal pulmonary arterial circulation is known to differ from that of the adult in a significant manner. Pulmonary vascular resistance and impedance are extremely high in the immediate postpartum period and decline rapidly in the first few days of life [6]. The role of endogenous nitric oxide in this transition is only now being elucidated. Current evidence indicates that the endothelium is sufficiently mature to produce hemodynamically significant amounts of nitric oxide [7], and the underlying vascular smooth muscle is capable of vasodilating in response to both endogenous and inhaled nitric oxide [8]. The newborn circulation is also highly vasoreactive relative to the adult circulation [9] and is potentially more sensitive to small perturbations in normal blood gas parameters.
Clinically the newborn responses to hypercapnia and nitric oxide are of critical importance. Patients undergoing repair of complex cardiac defects are plagued by episodes of pulmonary hypertensive crisis in the postoperative period; these episodes can be precipitated by short periods of hypercapnia encountered during rewarming, shivering, or return of consciousness [10]. In addition, surgical manipulation of the pulmonary vessels and cardiopulmonary bypass creates potential endothelial dysfunction and makes an already highly reactive circulation even more susceptible to hypertension [11, 12]. This is particularly relevant as the trend toward earlier correction of many cardiac anomalies continues. The use of permissive hypercapnia and the addition of carbon dioxide to ventilator gases as treatment modalities make it critical to understand the deleterious effects of carbon dioxide and their potential reversibility with nitric oxide. These studies, therefore, define the regional responses to hypercapnia in a model of damaged pulmonary arterial endothelium and the subsequent response to inhaled nitric oxide.
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Material and Methods
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All animals received humane care in compliance with the Georgetown Animal Care and Use Committee and the "Principles of Laboratory Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Institutes of Health (NIH publication 85-23, revised 1985).
Surgical Preparation
Sixteen 48-hour-old (± 4 hours) Yorkshire piglets of either sex were used in this study. The ear vein was catheterized and animals were anesthetized with intravenous thiopental sodium (25 mg/kg). A half dose of this anesthetic agent was administered every 20 minutes to maintain an adequate level of anesthesia.
After endotracheal intubation the animals were placed in the supine position and mechanically ventilated with a pediatric positive-pressure ventilator (Health dyne 105, Marietta, GA). Throughout the surgical preparation and during the collection of baseline data, an inspired oxygen fraction of 1.0 was used, and an arterial oxygen saturation of 93% or greater was maintained. Positive inspiratory pressure was preset between 15 and 25 cm H2O and the respiratory rate between 9 and 10 ventilations/min. These ventilatory settings achieved an arterial carbon dioxide tension between 25 and 30 mm Hg. To prevent atelectasis, a positive end-expiratory pressure of 3 cm H2O was maintained.
Pancuronium bromide (0.1 mg/kg intravenously every hour) was administered to produce complete muscle relaxation. A median sternotomy was performed, and the main pulmonary artery was dissected free from the aorta. A medium-sized titanium clip (Ethicon, Rochester, NY) was used to occlude the ductus arteriosus and effectively separate the pulmonary and systemic circulations. Sonomicrometry crystals for continuous measurement of diameter changes were placed on the lateral aspects of the main pulmonary artery with 4-0 silk sutures. An ultrasonic flow probe (Transonic Systems, Ithaca, NY) was placed around the most proximal portion of the pulmonary artery. A 6-mm ultrasonic flow probe (type 6S), chosen for best fit while avoiding constriction of the vessel, was used in all experiments. Care was taken to ensure that crystal movement was not affected by the flow probe. High-fidelity pressure transducers (model SPR-524; Millar Instruments, Inc, Houston, TX) were placed into the left atrial appendage and the main pulmonary artery. Each transducer was secured by a 4-0 silk pursestring suture. Premeasurement of the pulmonary artery catheter length in relation to the main pulmonary artery ensured that the transducer tip was positioned 2 mm beyond the ultrasonic flow probe to avoid any perturbation of waveforms. During each experiment, translingual arterial blood saturation, heart rate, and inspiratory and expiratory O2 and CO2 concentration were continually monitored. The surgical preparation and instrumentation are illustrated in Figure 1
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Fig 1. . Surgical preparation. A flow probe is placed around the main pulmonary artery. Pressure transducers are placed in the main pulmonary artery, left atrial appendage, and right carotid artery. Sonomicrometry crystals are shown in close-up in inset A. The final orientation of the pulmonary artery flow probe and pressure transducer is shown in inset B.
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Experimental Protocol
All animals underwent a 10-minute equilibration period after instrumentation was complete. Baseline data were then collected. Treated animals were then given N--nitro-L-arginine (L-NA; 20 mg/kg; Sigma Chemical Co, St. Louis, MO) via the internal jugular catheter. Control animals were given an equal volume of normal saline solution. Data were then collected at 3, 5, and 10 minutes after administration of either L-NA or vehicle. Animals then inhaled a premixed gas (Roberts Oxygen, Rockville, MD) containing a concentration of 15% CO2 balanced with oxygen for 10 minutes, and data were again collected at 3, 5, and 10 minutes. While the animal was still breathing the hypercapnic mixture, nitric oxide administration was begun through the inspiratory limb of the ventilator at a concentration of 100 parts per million (Roberts Oxygen). The dose was chosen based on our own dose-response curves (unpublished data) and the experience of others [13]. Ventilator tubing length was minimized to prevent formation of nitrogen dioxide compounds [14]. Data collection was repeated at 3-, 5-, and 10-minute intervals. To avoid the effects of respiratory motion on pulmonary artery pressure and flow, ventilation was briefly interrupted during data collection intervals without any observable changes in pulmonary or systemic parameters [15]. Arterial blood oxygen tension, partial pressure of CO2, and pH were determined with a CIBA Corning analyzer (model 278; Medfield, MA) at each "10-minute" interval. Alveolar gas concentration (O2 and CO2 tension) and arterial oxygen saturation were constantly monitored with a pulse oximeter (POET II; Criticare Systems, Waukesha, WI). Nitric oxide levels were measured in the ventilator tubing as it entered the endotracheal tube with an electrochemical monitor (Pac II NO monitor; Dräger, Inc, Chantilly, VA).
Data Collection and Analysis
The signal generation of high-fidelity pressure waveforms was electronically processed through a calibration control unit (Millar, Inc, Houston, TX) and a Gould transducer (model 13; Cleveland, OH). The analog signals were amplified, transmitted, and temporarily stored in an IBM 486 PS model 30 computer for analog-to-digital conversion at a sampling rate of 200 Hz. Ultrasonic flow probe signals were processed and amplified through a Transonic flowmeter system (model T-201) and transmitted to the same computer for analog-to-digital conversion. Simultaneous analog pressure and flow waveforms were displayed on an oscilloscope (model 5B10; Tektronic, Beaverton, OR) for signal verification during experimental manipulation. Data were subsequently downloaded onto a Dell 25 MHz 486x PC with a math coprocessor for Fourier analysis and hemodynamic computations. Between five and ten heart beats were analyzed per data collection interval per animal, resulting in 120 to 240 heart beats that underwent analysis per data collection interval.
Hemodynamic Calculations
PULMONARY VASCULAR RESISTANCE, INPUT MEAN, AND CHARACTERISTIC IMPEDANCE.
Pulmonary vascular resistance was calculated in the usual fashion: 
PA - LA/
PA, where PA is the mean pulmonary artery pressure, LA is the mean left atrial pressure, and PA is the mean pulmonary artery flow.
Pulmonary arterial impedance calculations were based on a Fourier analysis of pressure and flow waves as previously described [16]. Data collection periods were 30 seconds long, and eight to 16 random heart beats were analyzed for each data interval for each pig. Ten harmonics were calculated for each heart beat. Total pulmonary flow is expressed as:
where Qm is the mean flow, Qn is the amplitude of the nth harmonic, is the fundamental angular frequency (2
f where f is the frequency in Hz), t is the length of the sequence, and 
n is the phase angle of the nth harmonic. Pressure waveforms are expressed as:
where Pm is the mean pressure, Pn is the amplitude of the nth harmonic, and ßn is the phase angle of the nth harmonic. Dividing mean pressure by mean flow produces the input impedance (Zm) at the zeroth harmonic. Similarly, the division of each of the sinusoidal terms gives the input impedance for the nth harmonic. The corresponding phase angle (
n) was calculated from subtraction of the flow phase angle from the pressure phase angle. Characteristic impedance (Zo) is defined as the impedance in the absence of wave reflections and was calculated between 3 and 10 Hz.
DERIVATION OF INSTANTANEOUS ELASTICITY MEASUREMENTS.
Wave velocity (Co) was calculated for the main pulmonary artery assuming the relationship Womersley derived between characteristic impedance, wave velocity, and radius (R) of a strongly tethered elastic tube [17]:
where 
= 1.055g/mL, which is the density of blood; 
= 0.5, which is Poisson's ratio; and j = 
-1. M10 and 
are functions of Womersley's nondimensional parameter 
:
where µ = 0.04 poise, which is fluid viscosity.
Using the calculated Womersley's wave velocity from above, a value for the elastic modulus (E
) is determined by substitution using the Moens-Korteweg equation [16]:
where h = wall thickness.
Statistical Analysis
All statistical analyses were performed using a computer-based software package (Instat; George Washington University, Washington, DC). A paired two-tailed nonparametric test (Mann-Whitney U) was employed to determine statistical significance within groups. An unpaired two-tailed Mann-Whitney U was used to determine significance between groups. A p value equal to or less than 0.05 was considered statistically significant.
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Results
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Response to L-NA
Treatment with L-NA caused an increase in pulmonary artery pressure, but no change in pulmonary artery flow. This resulted in an increase in pulmonary vascular resistance and input mean impedance (Table 1). No alteration was seen in characteristic impedance, modulus of elasticity, or radius. None of the blood gas parameters were altered (Table 2).
Response to Hypercapnia
Inhalation of hypercapnic gas resulted in a significant increase in arterial CO2 tension and decrease in pH in both groups. The hypercapnic challenge also resulted in a decrease in arterial oxygen tension, although the oxygen saturations remained greater than 93% throughout all experiments (see Table 2
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In control animals, hypercapnia caused an increase in pulmonary artery pressure and flow. Pulmonary vascular resistance and input mean impedance were also increased (Fig 2). Characteristic impedance was not altered. The radius of the main pulmonary artery increased during hypercapnia, but was associated with no alteration in the modulus of elasticity. Animals treated with L-NA before the hypercapnic challenge also underwent large increases in pulmonary artery pressure, pulmonary vascular resistance, and Zm. Unlike the control animals, flow did not increase, but rather underwent a significant decrease. Treated animals underwent larger increases than control animals with regard to pulmonary artery pressure (93% versus 67%; p < 0.05), pulmonary vascular resistance (193% versus 39%; p < 0.01), and Zm (188% versus 37%; p < 0.01). Also unlike the control animals, Zo increased with an associated increase in both the radius and modulus of elasticity of the proximal pulmonary vasculature.
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Fig 2. . Impedance moduli and corresponding phase angles in control animals. Input mean impedance is at zero Hz and increases with hypercapnia. It decreases with nitric oxide inhalation. Characteristic impedance is between 3 and 10 Hz and is not altered by hypercapnia or nitric oxide.
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Response to Nitric Oxide
Upon inhalation of nitric oxide, pulmonary artery pressure, pulmonary vascular resistance, and Zm decreased. Nitric oxide did not return these values completely to baseline values in either group, but in the L-NA group it did return to values very near those after administration of L-NA. The changes were larger in the treated animals when compared with controls for pulmonary artery pressure (49% versus 23%; p < 0.05), pulmonary vascular resistance (63% versus 14%; p < 0.05), and Zm (62% versus 12%; p < 0.05). Pulmonary artery flow was unchanged in control animals. Flow tended to increase in the treated animals, but this change did not reach significance (3.50 ± 0.6 versus 4.03 ± 0.7 mL/s; p = 0.0625). Characteristic impedance also decreased, and was associated with a decrease in radius and modulus of elasticity (see Table 1). Nitric oxide did not improve arterial CO2 tension or pH in either group, but improved arterial oxygen tension in both groups (see Table 2).
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Comment
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Despite a long clinical experience, pulmonary hypertensive crisis in the pediatric cardiac surgery population remains without a consistent and reproducibly effective treatment regimen. Although the pathophysiology has not been fully elucidated, it is well known that rising levels of arterial carbon dioxide can precipitate crises during the critical early postoperative period [18]. In addition, surgical manipulation and cardiopulmonary bypass potentially damage the vascular endothelium and exacerbate the response to hypercapnia [12]. Further impetus to fully define the response to hypercapnia in the face of a nonfunctioning endothelium comes from the clinical applications of carbon dioxide in balancing the systemic and pulmonary circulations in single-ventricle physiology [19], as well as the use of permissive hypercapnia to reduce barotrauma in mechanically ventilated patients [5]. The studies described herein define the response of the neonatal pulmonary arterial circulation to increased levels of arterial carbon dioxide in the presence of an endothelium unable to produce endogenous nitric oxide, and define the ability of inhaled nitric oxide to reverse the associated pulmonary arterial vasoconstriction.
Piglet Model and Pulmonary Impedance
The newborn pulmonary arterial circulation is characterized by high pressure, resistance, and impedance values that rapidly decrease in the first hours and days of life. This is accompanied by a concomitant increase in pulmonary arterial flow from very low levels [6]. Experimentally, the piglet has been shown to closely parallel the human circulation during the first 3 months of life with regard to normal hemodynamic maturation and morphometric growth, providing an excellent model of the pulmonary arterial circulation in which to study hypertensive disease. [20]. Hydraulic impedance analysis accounts for the pulsatile nature of blood flow, and allows for quantification of energy not measured by mean terms (ie, resistance). In the neonatal heart these pulsatile terms can account for as much as 50% of right heart work [21]. Input mean impedance is highly analogous to vascular resistance and quantifies changes occurring at the arteriolar level, a region not well studied by traditional in vitro methodology. These data can be compared with changes in Zo, which is not influenced by reflected waves and therefore represents alterations in the more proximal vessels. Decreases in Zo represent a "relaxation" of the larger vessels that can occur secondary to passive increases in vessel diameter or from a primary decrease in the modulus of elasticity (or "stiffness") of the vessel wall. To this end, direct, real time measurements of the diameter changes occurring in the main pulmonary artery can be compared with calculated values for elasticity to define the changes in Zo.
Role of the Vascular Endothelium
The use of the nitric oxide synthase inhibitor L-NA in our animals caused significant alterations in resting pulmonary arterial hemodynamics. The increase in pulmonary vascular resistance and Zm represent arteriolar vasoconstriction from inhibition of endogenous nitric oxide production. The larger, conductance vessels are not dependent on endogenous nitric oxide for maintenance of resting tone, as demonstrated by the unaltered Zo (Fig 3). Although Furchgott and Zawadzki's [22] pioneering work implied nitric oxide's role in the maintenance of normal hemodynamics, subsequent animal studies have further defined the its role in both the maturation and maintenance of hemodynamics in the newborn pulmonary arterial circulation. Fetal and newborn sheep respond to inhalation of nitric oxide, implying that the vascular smooth muscle is responsive to the vasodilatory effects of nitric oxide very early in development [8]. Studies involving use of the endothelial-independent vasodilator sodium nitroprusside indicate that no significant difference exists in the reactivity of the vascular smooth muscle when fetal and neonatal animals are compared [23, 24]. In contrast, these studies noted an increase in the response to the endothelium-dependent vasodilator acetylcholine with increasing age, demonstrating maturational differences in endothelial cell function. These observations can be explained by a relatively immature endothelium, unable to produce significant amounts of nitric oxide in response to acetylcholine. The more likely explanation is that the endothelium is functioning at maximum capacity and cannot increase nitric oxide production in response to endothelium-dependent vasodilators. Our studies support the latter contention, and the assertion that the endothelium plays a critical early role in maintenance of pulmonary arterial hemodynamics, because administration of L-NA resulted in a hypertensive response even in these very young animals.
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Fig 3. . Impedance moduli and corresponding phase angles in N--nitro-L-arginine (L-NA)-treated animals. Data before L-NA are not shown for clarity. Input mean impedance is at zero Hz and increases with hypercapnia; the response is potentiated when compared with controls and decreases with nitric oxide inhalation. Characteristic impedance is between 3 and 10 Hz and increases with hypercapnia and decreases with nitric oxide.
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CO2 in the Neonatal Pulmonary Arterial Circulation
Pulmonary hypertension secondary to hypercapnia occurs in the pediatric intensive care unit both as an inadvertent respiratory complication, and as a therapeutic modality. This striking duality makes a thorough understanding of its effects on the pulmonary circulation critical. The rationale behind its use as a therapeutic agent is the desired increase in vascular resistance caused by breathing the hypercapnic gas [19]. However, inadvertent episodes of hypercapnia during rewarming and while awakening from anesthesia can result in unanticipated increases in resistance [10] and impedance. And, as Domkowski and associates [25] showed, even very brief episodes of hypercapnia can cause persistent elevations in characteristic impedance under the influence of specific anesthetic regimens. This dramatic increase in right ventricular work may lead to right ventricular failure in the neonatal heart that often is functioning near maximal capacity. Whereas careful titration with sodium bicarbonate has been shown to ameliorate the vasoconstrictor effects of acidosis in infants after cardiopulmonary bypass [26], inhaled nitric oxide in our experiments rapidly and effectively reversed the hypertension associated with respiratory acidosis in spite of a persistently low pH. In our study hypercapnia produced a strong proximal vasoconstriction in both groups. The hypertensive response was much more pronounced in the L-NA–treated group, with pressure nearly doubling, and pulmonary vascular resistance and Zm trebling (see Fig 3). The imposed endothelial dysfunction also resulted in an increase in Zo not seen in control animals. In this instance the radius of the vessel actually increased, or "dilated," secondary to the large increase in the transmural distending pressure. Therefore, the increase in Zo is a result of the nearly tenfold increase in stiffness of the proximal vessels as measured by the modulus of elasticity. This increase in load presented to the right ventricle is prevented in the presence of an intact endothelium and reversed by the addition of inhaled nitric oxide under conditions of endothelial dysfunction. The consequences of this ventricular-vascular mismatching during hypercapnia can clearly be seen in the decrease in flow noted in the treated group, a decrease not seen in control animals. Pulmonary artery flow actually increased in our control animals with hypercapnia, consistent with studies in human subjects; this may be partially a result of endogenous catecholamine release [27]. Two possible explanations exist for the altered response we observed in L-NA–treated animals. The combination of the larger increase in input mean impedance coupled with the increase in characteristic impedance may produce such a large pulmonary vasoconstrictor response that the compensatory increase in cardiac output cannot occur. Alternatively, endogenous nitric oxide from either the pulmonary circulation or the myocardium itself may be required for the increase in flow. One of the advantages of pulsatile hemodynamic analysis is that it is frequency dependent and therefore describes pulmonary arterial hemodynamics independent of flow [28].
Response of Hypercapnic Vasoconstriction to Inhaled Nitric Oxide
The introduction of inhaled nitric oxide as a therapeutic modality has caused cautious optimism for surgeons treating patients with pulmonary hypertensive disease. In our study, nitric oxide lowered the elevated pulmonary vascular resistances and input mean impedances secondary to hypercapnia in both groups of animals. However, in neither group did it lower these measures of arteriolar vasoconstriction to baseline values. Similarly, the proximal vasoconstriction seen in the L-NA–treated animals was relieved, with a resultant trend toward increasing pulmonary artery flow (3.50 ± 0.6 v. 4.03 ± 0.7 mL/s; p = 0.625). This indicates some mechanism in addition to perturbation of the nitric oxide system was responsible for the vasoconstrictor response. This is also suggested by the observation that nitric oxide decreased input mean impedance to approximately the levels measured after administration of L-NA, but not to baseline (pre–L-NA) levels. Because our study did not correct for acidosis, the altered pH almost certainly had direct effects on the vascular smooth muscle, making the response to nitric oxide incomplete. Because pH would be corrected in the postoperative patient it seems reasonable to assume that inhaled nitric oxide would be even more efficacious in that setting. And, although pH and arterial CO2 tension were not altered by nitric oxide inhalation, arterial oxygen tension was increased-a desired result in the treatment of pulmonary hypertensive crisis. These findings indicate several positive aspects of the use of nitric oxide in the treatment of neonatal cardiac surgery patients. First, the deleterious vasoconstrictor effects seen with inadvertent and transient episodes of hypercapnic acidosis can perhaps be avoided in patients receiving nitric oxide in the immediate postoperative period. Second, although endothelial dysfunction markedly exacerbates the response to hypercapnia, inhaled NO remains effective as a vasodilator. And, finally, inhaled nitric oxide improves oxygenation in the presence of hypercapnic acidosis.
Conclusions
These studies demonstrate several important findings in a neonatal model of pulmonary arterial endothelial damage with subsequent exposure to hypercapnia and inhaled nitric oxide. The vascular endothelium modulates resting hemodynamics in the distal arteriolar region of the newborn pig, but does not perform a similar role in larger, more proximal vessels. Animals with L-NA–induced endothelial dysfunction undergo exaggerated vasoconstrictor responses in the face of hypercapnic acidosis. Additionally, the inhibition of endogenous nitric oxide reduces the compliance of the proximal arteries in response to hypercapnia, with a significant impact on ventricular dynamics. Finally, inhaled nitric oxide effectively reverses the changes induced by hypercapnic ventilation and improves oxygenation, even in the face of severe endothelial dysfunction.
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Footnotes
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Presented at the Poster Session of the Thirty-Second Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Jan 29–31, 1996.
Address reprint requests to Dr Hopkins, Cardiothoracic Surgery, Brown University, The Miriam Hospital, 164 Summit Ave, Providence, RI 02906.
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Abstract
Introduction
