- Email: [email protected]
Effects of high frequency oscillatory ventilation compared to conventional ventilation upon pulmonary vascular prostanoid production in neonatal piglets
Prostaglandins Lcukotriencs and Nedicinc 17: 107-115, 1985
EFFECTS OF HIGH FREQUENCY OSCILLATORY VENTILATION COMPARED TO CONVENTIONAL VENTILATION UPON PULMONARY VASCULAR PROSTANOID PRODUCTION IN NEONATAL PIGLETS
John A. Mitchell,1 Robert S. Green,*g3y1 and Charles W. Lefflerl Departments of lPhysiology and Biophysics, *Pediatrics, and 30bstetrics and Gynecology, The University of Tennessee Center for the Health Sciences Memphis, Tennessee USA (reprint requests to CWL)
ABSTRACT In order to investigate the possibility that high-frequency oscillatory ventilation (HFO) might preferentially stimulate intrapulmonary prostacyclin (PGIR) synthesis thereby decreasing pulmonary vascular smooth muscle tone, we determined pulmonary prostacyclin and thromboxane production in neonatal piglets ventilated by conventional means and by HFO (8 Hz). There was no detectable release of prostacyclin or thromboxane into blood passing through the lungs (i.e., pulmonary arterial concentration8 were greater than aortic concentrations) during ventilation by conventional means or during HFO. Furthermore, there were no differences between the two modes of ventilation in cardiac output, systemic or pulmonary vascular resistance, or pulmonary vascular response to hypoxia/hypercapnia. We conclude that HFO does not stimulate pulmonary prostacyclin production and does not affect pulmonary vascular resistance or the pulmonary vasoconstriction associated with alveolar hypoxialhypercapnia when compared to conventional ventilation in anesthetized newborn piglets.
107
INTRODUCTION -____ Conventional mechanical ventilation (CV) is accomplished using tidal volumes and respiratory rates similar to those observed in normal spontaneous ventilation. Recently, several investigators (l-5) have reported effective ventilation with tidal volumes approximating or even substantially less than dead space by using frequencies varying from 2 to 30 Hz. Bohn et al (1) reported effective ventilation of dogs for a prolonged period while using high-frequency oscillation. Others have had success with HFO in infants with respiratory difficulties (2,5-o) and with adults under a variety of conditions requiring ventilatory assistance (3,5). Tissue distortion has been known for some time to augment prostaglandin synthesis (7). In particular, mechanical hyperinflation stimulates intrapulmonary synthesis of PG12 (8). Furthermore, PG12 production by the pulmonary vasculature of neonatal (9) and adult (10,111 animals has been shown to increase in response Therefore, to hypoxic pulmonary vasoconstriction. we hypothesized that HFO, when compared to CV, would augment PG12 synthesis and thereby result in a decreased pulmonary pressor response to combined hypoxia/hypercapnia. METHODS Animal Preparation Neonatal piglets, one to three days postnatal (1.5 f 0.1 [SEMI kg; standard error of the mean; n = 10) were anesthetized with ketamine (7 mg/kg I.M.) and xylazine (0.2 mg/kg I.M.). They were maintained on chloralose (70 mg/kg initially plus 15 mg/kg/hr). Catheters were placed in the descending aorta through a femoral artery, in the abdominal vena cava through a femoral vein, and in a thoracic vena cava through the other femoral vein. The trachea was cannulated percutaneously, and ventilation was begun (Harvard intermediate animal ventilator) using room air and supplemental The oxygen with a positive end expiratory pressure of 2 cm H20. heart and pulmonary artery were exposed via a left thoracotomy An electromagnetic flow through the fourth intercostal space. cuff was placed around the main pulmonary artery distal to the pulmonic valve. Catheters were placed in the left atrium through the left atria1 appendage and in the main pulmonary artery just distal to the flow cuff. The chest wall was approximated by tying the ribs back since positive airway pressure was together; maintained, the lung and chest wall remained in contact throughout the experiments. Systemic and pulmonary arterial pressures, left atria1 pressure, central venous pressure, and right ventricular output were continuously measured and recorded on a direct writing recorder. Left ventricular output was assumed to be equal to right ventricular output since the ductus was closed and left atria1 pressure exceeded right atria1 pressure, making foramen shunting unlikely. Arterial blood gases and pH were determined
108
frequently, and intravenous sodium bicarbonate solution was base deficit of necessary to maintain a administered as Hyperinflations (SO-75 ml) were given to approximately zero. prevent patchy atelectasis upon changing mode of ventilation and three to five minutes following hypoxic/hypercapnic treatment (see below). Mechanical Ventilation Conventional mechanical ventilation was achieved with a rate between 20-25 breaths per minute and a tidal volume of 18 to 25 ml per breath in order to achieve an arterial PC02 of 35 to 40 Once this was accomplished, conventional ventilatory mm Hg. parameters were not changed for the remainder of the experiment. As noted, a positive end expiratory pressure of 2 cm Ii20 was maintained during conventional ventilation. A piston pump was employed to deliver high frequency oscillation. The frequency generated by this pump was 8 Hz (480 cycles/minute), and the volume delivered was 5.5 ml/stroke. The HFO was superimposed upon a humidified bias flow (Figure 1). Since
.-Bias
Flow
I DEAD
PIGLET
SPACE
1 Fig.
1
RESISTOR
Figure 1. Schematic representation of the apparatus used ventilate neonatal piglets by high-frequency oscillation.
to
a portion of each delivered stroke escapes through the resistor, the actual volume delivered to the lungs is less than 5.5 ml/stroke. Tracheal pressure was measured from a sidearm of the ventilatory
109
tubing proximal to the tracheostomy tube. The bias flow was adjusted so that the mean airway pressure was the same during both HFO and CV. Depending upon the size of the piglet, the dead space between the bias flow and the animal was modified from 1.0 to 1.5 ml so that the arterial Pco2 was maintained between 35 and 40 mm Hg. The same flow of oxygen that entered the bias flow during HFO was added to room air as inflow into the conventional ventilator. Experimental
Protocol
Following instrumentation and a 15-minute equilibration period, the experimental protocol was carried out as follows: Each piglet was studied during three consecutive 30-minute periods. Within each of these periods, there was an initial 15-minute baseline, a 3-minute treatment with hypoxic/hypercapnic ventilation, and a final 12-minute interval for return to baseline. Baseline measurements and blood samples (see below) were drawn immediately prior to each 3-minute period of hypoxic/hypercapnic ventilation, and an additional set of blood samples was drawn at the end of each 3-minute hypoxiclhypercapnic treatment. Ventilation during the first and third 30-minute periods was with the same mode, either CV or HFO, and period 2 was with the alternate mode of ventilation. Assignment of piglets to these two different orders of ventilation was randomized to negate any bias that might be with vasculature's responsiveness to associated the pulmonary Values the first, second, or third exposure to hypoxia/hypercapnia. of the first and third periods were averaged for each animal. The hypoxic/hypercapnic challenge was accomplished using a mixture of 12% 02 and 5% CO2. Hypercapnia was combined with hypoxia because we determined in preliminary experiments that 12% 02 alone gave poor pulmonary vasoconstriction, and lower FiO2 was not tolerated well by the neonatal piglets. Similarly, longer exposure to the hypoxic/hypercapnic mixture was poorly tolerated. the following blood samples were At each sampling period, a 0.4 ml sample from the aorta for blood gas and pH analysis drawn: and samples of 1 ml each from the pulmonary artery and aorta for radioimmunoassay (RIA) of prostanoids. measured gases and pH were using an Arterial blood Laboratory blood gas analyzer. Radioixnmunoassay Instrumentation of 6-keto-PGFl, and thromboxane B2 were performed following liquid extraction as described previously.12p13 In two chromatographic was determined also using the same piglets, F'GE2 concentration methods. Data are reported as mean f standard error of the mean. Comparisons between groups were made using the t-test on paired P <0.05 was required for inference that two populations samples. were different.
110
HFO did not change pulmonary arterial pressure, left atria1 pressure, cardiac output, systemic arterial pressure, systemic vascular resistance or calculated pulmonary vascular resistance when compared with CV during normoxia/normocapnia (Figures 2 and pulmonary vasoconstriction in response to combined Furthermore, 3).
12%02. 3or
5%002
E
10
(mmHg) LAP
o
& __-- -P.----f-
---A
,sL--_o
120 J
110
--_.
(mI/~~~kg)roo f so
____
---
1
-++---4 Y
w
60
SAP (mmHg)
+--/k-d
40 20 0-w
1
p
: ---+----
0
1
2
TIME
3
10
(mid
Figure 2. ventilation Effect of with 12% 0215% co2 (hypoxia/hypercapnia) upon pulmonary arterial pressure (PAP), left atria1 pressure (LAP), systemic arterial pressure (SAP), and cardiac output (CO) during conventional ventilation (0) and high-frequency oscillation (01.
111
,600
cv HFO
-
.400
UJI
t
,150 ,100 1
capnia
Normoxia Normacapnla
capnia (3min)
H ypoxia t-lypercapnia (3min)
Figure 3. Effect of ventilation with 12% 0215% CO2 (hypoxia/hypercapnia) upon pulmonary vascular resistance and systemic vascular resistance during conventional ventilation (CV> or high-frequency oscillation (HFO). PVR = pulmonary vascular resistance. SVR = systemic vascular resistance. *P <0.05 compared to ventilation with 02 enriched air (normoxia/normocapnia).
hypoxialhypercapnia during HFO was not significantly different (P = 0.07) from the response to the same stimulus during CV. The administration of 12% 0215% CO2 during periods of CV to neonatal piglets increased pulmonary arterial pressure 90 f 15% without significantly changing left atria1 pressure, cardiac output, or systemic arterial pressure (Figure 2). The calculated pulmonary vascular resistance increased 122 f 14% (Figure 3). Similar effects (P >0.05) were observed exposure to alveolar upon while HFO. HFO, hypoxia/hypercapnia ventilating with During pulmonary arterial pressure increased 72 f 15%. Pulmonary vascular resistance increased 78 f 23%. Changes in left atria1 pressure, cardiac output, and systemic arterial pressure were not significant.
112
HFO compared to CV did not alter arterial blood gases during either normoxia (pll 7.44 f 0.02, Po2 188 f 15 mm Hg, Pco2 35 f 1 mm Hg with CV versus pH 7.42 f 0.01, Pop 145 f 15 mm Hg, Pco2 33 f 2 mm Hg with HFO) or during hypoxic/hypercapnic ventilation (pH 7.30 f 0.02, Po2 40 f 3 mm Hg, Pco2 50 f 3 mm Hg with CV versus pH 7.31 f 0.02, Po2 44 f 4 nmtHg, Pco2 47 f 3 rmnHg with HFO). Plasma 6-keto-PGFl, and TXB2 concentrations were similar at about 300-400 pg/ml (Table I). Plasma PGE2 was not detectable
TABLE I. Pulmonary arterial (PA) and aortic (AO) blood concentrations of PG12 plus 6-keto-PGFl (PGI) and TXA2 plus TXB2 (TX) during ventilation with 92 enriched air (normoxia/normocapnia)and during ventilation with 12% 0215% CO2 (hypoxiafhypercapnia) in anesthetized neonatal piglets (N = 5).
PGI (pg/ml) A0 PA
TX (pg/ml) PA A0
Conventional Ventilation Normoxia/Normocapnia Hypoxia/Hypercapnia
310 f 43 448 f 61
291 f 41 264 f 72
324 f 97 399 f 67 395 f 115 314 f 65
High Frequency Oscillation Normoxia/Normocapnia Hypoxia/Hypercapnia
294 f 54 289 f 75 426 f 102 322 f 66
371 f 94 352 f 104 359 f 120 458 f 101
(<13 pg/ml) in these neonatal piglets. The method of ventilation (CV or HFO) had no effect upon plasma PG12 or thromboxane concentration. Net pulmonary PG12 production was not detectable (aorta concentration was less than pulmonary arterial 6-keto-PGFlo concentration) under any conditions used in the present experiments. DISCUSSION HFO has proven to be an effective mode of ventilation under a variety of circumstances (l-5). The present study was designed to evaluate how HFO affects prostanoid synthesis and hemodynamics during a period of alveolar hypoxia combined with mild hypercapnia. We hypothesized that HFO would augment pulmonary vascular proetacyclin synthesis and thus attenuate the pulmonary vasoconstrictor response to hypoxia/hypercapnia. However, we observed no significant effects of HFO on either pulmonary vascular PG metabolism or pulmonary hemodynamics. These findings suggest that, despite the very rapid ventilatory rate, the low tidal volumes
113
employed in HFO do not result in enough tissue distortion to alter arachidonic acid release and PG synthesis. There appear to be no significant hemodynamic effects of HFO, other than the absence of "respiratory variation" in the pressure and flow signals. We (13) and others (10,ll) have reported that alveolar hypoxia stimulates intrapulmonary synthesis of PGI2, a potent vasodilator, which may attenuate the vasoconstriction (13,141. In the present study, we could detect no difference in the net pulmonary production of PG12 or normoxia thromboxane during compared to cited hypoxia/hypercapnia. The experiments above, in which stimulation of pulmonary PG12 production by alveolar hypoxia was detected, used lungs perfused with physiological salt solution, allowing the entire pulmonary venous efflux to be collected. Further, the pulmonary arterial prostacyclin concentration was zero, permitting changes in pulmonary production to be detected pulmonary arterial readily. In present experiments, the radioimmunoassayable 6-keto-PGFlo was greater than pulmonary venous concentration indicating a net uptake of prostacyclin or 6-keto-PGFl, by the lung and obscuring any changes in intrapulmonary synthesis when only inflow and output concentrations were determined. Other investigators have reported no differences in either surfactant production or in lung morphology after periods of HFO (14,151. We detected no difference in prostanoid production or significant difference in the pulmonary response to combined alveolar hypoxia/hypercapnia dependent upon the mode of ventilation. We observed nothing that would contraindicate the use of HFO as an alternative mode of mechanically assisted ventilation. ACKNOWLEDGEMENTS technical assistance The authors acknowledge the excellent of Stephanie Adams and Mildred Jackson for their expert technical help and Rosalind Griffin for excellent secretarial assistance. Investigator of the American Dr. Leffler is an Established Heart Association with funds contributed in part by the Tennessee The research was supported by grants from the American Affiliate. Heart Association with funds contributed in part by the Tennessee Affiliate, The Tennessee Lung Association, the National Institutes of Health (AMO74051, and The University of Tennessee College of Medicine (Biomedical Research Support Grant). REFERENCES 1.
Bohn D, Miyasaka K, Marchak B, Thompson W, Froese A, Bryan Journal of A. Ventilation by high-frequency oscillation. Applied Physiology 48:710, 1980.
2.
Franz I, Westhammer J, Stark A. High-frequency ventilation in Adequate gas exchange premature infants with lung disease: at low tracheal pressure. Pediatrics 71:483, 1983.
114
3.
Sjostrand U. Summary of experimental and clinical features of high-frequency positive-pressure ventilation - HFPPV. Acta Anaesthesiologica Scandinavica 64:165, 1977.
4.
Slutsky A, Kamm R, Rossing T, Loring S, Lehr J, Shapiro A, Ingram R, Drazen J. Effects of frequency, tidal volume, and lung volume in CO2 elimination in dogs by high frequency (2-30 Hz), low tidal volume ventilation. Journal of Clinical Investigation 68:1475, 1981.
5.
Butler W, Bohn D, Bryan A, Froese A. frequency oscillation in humans. 59:577, 1980.
6.
Marchak B, Thompson W, Duffty P, Miyaki T, Bryan M, Froese A. Treatment of RDS by high-frequency oscillatory ventilation: A preliminary report. The Journal of Pediatrics 99:287, 1981.
7.
Piper P, Vane J. The release of prostaglandins from lung and other tissues. Annals of the New York Academy of Sciences 180:363, 1971.
8.
Said S. Pulmonary metabolism of prostaglandins and vasoactive peptides. Annual Review of Physiology 44:257, 1982.
9.
Green RS, Leffler CW. Hypoxia stimulates prostacyclin synthesis by neonatal lungs. Pediatric Research (in press).
10.
Voelkel N, Gerber J, McMurtry I, Nies A, Reeves J. Release of vasodilator prostaglandin, PG12, from isolated rat lung during vasoconstriction. Circulation Research 48:207, 1981.
11.
Hamasaki Y, Tai H, Said S. Hypoxia stimulates prostacyclin generation by dog lung -in vitro. Prostaglandins Leukotrienes and Medicine 8:311, 1982.
12.
Leffler C, Hessler J, Green R. Surgery increases fetal prostacyclin. Prostaglandins 24:387, 1982.
13.
Leffler C, Hessler J, Green R. The onset of breathing at birth stimulates pulmonary vascular prostacyclin synthesis. Pediatric Research (in press).
14.
Frantz I, Stark A, Davis J, Davies P, Kitzmiller T. Highfrequency ventilation does not affect pulmonary surfactant, liquid, or morphologic features in normal cats. American Review of Respiratory Diseases 126:909, 1982.
15.
Truog W, Standaert T, Murphy J, Palmer S, Woodrum D, Hodson W. Effect of high-frequency oscillation on gas exchange and pulmonary phospholipids in experimental hyaline membrane disease. American Review of Respiratory Diseases 127:585, 1983.
115
Ventilation of highAnesthesia and Analgesia
EFFECTS OF HIGH FREQUENCY OSCILLATORY VENTILATION COMPARED TO CONVENTIONAL VENTILATION UPON PULMONARY VASCULAR PROSTANOID PRODUCTION IN NEONATAL PIGLETS
John A. Mitchell,1 Robert S. Green,*g3y1 and Charles W. Lefflerl Departments of lPhysiology and Biophysics, *Pediatrics, and 30bstetrics and Gynecology, The University of Tennessee Center for the Health Sciences Memphis, Tennessee USA (reprint requests to CWL)
ABSTRACT In order to investigate the possibility that high-frequency oscillatory ventilation (HFO) might preferentially stimulate intrapulmonary prostacyclin (PGIR) synthesis thereby decreasing pulmonary vascular smooth muscle tone, we determined pulmonary prostacyclin and thromboxane production in neonatal piglets ventilated by conventional means and by HFO (8 Hz). There was no detectable release of prostacyclin or thromboxane into blood passing through the lungs (i.e., pulmonary arterial concentration8 were greater than aortic concentrations) during ventilation by conventional means or during HFO. Furthermore, there were no differences between the two modes of ventilation in cardiac output, systemic or pulmonary vascular resistance, or pulmonary vascular response to hypoxia/hypercapnia. We conclude that HFO does not stimulate pulmonary prostacyclin production and does not affect pulmonary vascular resistance or the pulmonary vasoconstriction associated with alveolar hypoxialhypercapnia when compared to conventional ventilation in anesthetized newborn piglets.
107
INTRODUCTION -____ Conventional mechanical ventilation (CV) is accomplished using tidal volumes and respiratory rates similar to those observed in normal spontaneous ventilation. Recently, several investigators (l-5) have reported effective ventilation with tidal volumes approximating or even substantially less than dead space by using frequencies varying from 2 to 30 Hz. Bohn et al (1) reported effective ventilation of dogs for a prolonged period while using high-frequency oscillation. Others have had success with HFO in infants with respiratory difficulties (2,5-o) and with adults under a variety of conditions requiring ventilatory assistance (3,5). Tissue distortion has been known for some time to augment prostaglandin synthesis (7). In particular, mechanical hyperinflation stimulates intrapulmonary synthesis of PG12 (8). Furthermore, PG12 production by the pulmonary vasculature of neonatal (9) and adult (10,111 animals has been shown to increase in response Therefore, to hypoxic pulmonary vasoconstriction. we hypothesized that HFO, when compared to CV, would augment PG12 synthesis and thereby result in a decreased pulmonary pressor response to combined hypoxia/hypercapnia. METHODS Animal Preparation Neonatal piglets, one to three days postnatal (1.5 f 0.1 [SEMI kg; standard error of the mean; n = 10) were anesthetized with ketamine (7 mg/kg I.M.) and xylazine (0.2 mg/kg I.M.). They were maintained on chloralose (70 mg/kg initially plus 15 mg/kg/hr). Catheters were placed in the descending aorta through a femoral artery, in the abdominal vena cava through a femoral vein, and in a thoracic vena cava through the other femoral vein. The trachea was cannulated percutaneously, and ventilation was begun (Harvard intermediate animal ventilator) using room air and supplemental The oxygen with a positive end expiratory pressure of 2 cm H20. heart and pulmonary artery were exposed via a left thoracotomy An electromagnetic flow through the fourth intercostal space. cuff was placed around the main pulmonary artery distal to the pulmonic valve. Catheters were placed in the left atrium through the left atria1 appendage and in the main pulmonary artery just distal to the flow cuff. The chest wall was approximated by tying the ribs back since positive airway pressure was together; maintained, the lung and chest wall remained in contact throughout the experiments. Systemic and pulmonary arterial pressures, left atria1 pressure, central venous pressure, and right ventricular output were continuously measured and recorded on a direct writing recorder. Left ventricular output was assumed to be equal to right ventricular output since the ductus was closed and left atria1 pressure exceeded right atria1 pressure, making foramen shunting unlikely. Arterial blood gases and pH were determined
108
frequently, and intravenous sodium bicarbonate solution was base deficit of necessary to maintain a administered as Hyperinflations (SO-75 ml) were given to approximately zero. prevent patchy atelectasis upon changing mode of ventilation and three to five minutes following hypoxic/hypercapnic treatment (see below). Mechanical Ventilation Conventional mechanical ventilation was achieved with a rate between 20-25 breaths per minute and a tidal volume of 18 to 25 ml per breath in order to achieve an arterial PC02 of 35 to 40 Once this was accomplished, conventional ventilatory mm Hg. parameters were not changed for the remainder of the experiment. As noted, a positive end expiratory pressure of 2 cm Ii20 was maintained during conventional ventilation. A piston pump was employed to deliver high frequency oscillation. The frequency generated by this pump was 8 Hz (480 cycles/minute), and the volume delivered was 5.5 ml/stroke. The HFO was superimposed upon a humidified bias flow (Figure 1). Since
.-Bias
Flow
I DEAD
PIGLET
SPACE
1 Fig.
1
RESISTOR
Figure 1. Schematic representation of the apparatus used ventilate neonatal piglets by high-frequency oscillation.
to
a portion of each delivered stroke escapes through the resistor, the actual volume delivered to the lungs is less than 5.5 ml/stroke. Tracheal pressure was measured from a sidearm of the ventilatory
109
tubing proximal to the tracheostomy tube. The bias flow was adjusted so that the mean airway pressure was the same during both HFO and CV. Depending upon the size of the piglet, the dead space between the bias flow and the animal was modified from 1.0 to 1.5 ml so that the arterial Pco2 was maintained between 35 and 40 mm Hg. The same flow of oxygen that entered the bias flow during HFO was added to room air as inflow into the conventional ventilator. Experimental
Protocol
Following instrumentation and a 15-minute equilibration period, the experimental protocol was carried out as follows: Each piglet was studied during three consecutive 30-minute periods. Within each of these periods, there was an initial 15-minute baseline, a 3-minute treatment with hypoxic/hypercapnic ventilation, and a final 12-minute interval for return to baseline. Baseline measurements and blood samples (see below) were drawn immediately prior to each 3-minute period of hypoxic/hypercapnic ventilation, and an additional set of blood samples was drawn at the end of each 3-minute hypoxiclhypercapnic treatment. Ventilation during the first and third 30-minute periods was with the same mode, either CV or HFO, and period 2 was with the alternate mode of ventilation. Assignment of piglets to these two different orders of ventilation was randomized to negate any bias that might be with vasculature's responsiveness to associated the pulmonary Values the first, second, or third exposure to hypoxia/hypercapnia. of the first and third periods were averaged for each animal. The hypoxic/hypercapnic challenge was accomplished using a mixture of 12% 02 and 5% CO2. Hypercapnia was combined with hypoxia because we determined in preliminary experiments that 12% 02 alone gave poor pulmonary vasoconstriction, and lower FiO2 was not tolerated well by the neonatal piglets. Similarly, longer exposure to the hypoxic/hypercapnic mixture was poorly tolerated. the following blood samples were At each sampling period, a 0.4 ml sample from the aorta for blood gas and pH analysis drawn: and samples of 1 ml each from the pulmonary artery and aorta for radioimmunoassay (RIA) of prostanoids. measured gases and pH were using an Arterial blood Laboratory blood gas analyzer. Radioixnmunoassay Instrumentation of 6-keto-PGFl, and thromboxane B2 were performed following liquid extraction as described previously.12p13 In two chromatographic was determined also using the same piglets, F'GE2 concentration methods. Data are reported as mean f standard error of the mean. Comparisons between groups were made using the t-test on paired P <0.05 was required for inference that two populations samples. were different.
110
HFO did not change pulmonary arterial pressure, left atria1 pressure, cardiac output, systemic arterial pressure, systemic vascular resistance or calculated pulmonary vascular resistance when compared with CV during normoxia/normocapnia (Figures 2 and pulmonary vasoconstriction in response to combined Furthermore, 3).
12%02. 3or
5%002
E
10
(mmHg) LAP
o
& __-- -P.----f-
---A
,sL--_o
120 J
110
--_.
(mI/~~~kg)roo f so
____
---
1
-++---4 Y
w
60
SAP (mmHg)
+--/k-d
40 20 0-w
1
p
: ---+----
0
1
2
TIME
3
10
(mid
Figure 2. ventilation Effect of with 12% 0215% co2 (hypoxia/hypercapnia) upon pulmonary arterial pressure (PAP), left atria1 pressure (LAP), systemic arterial pressure (SAP), and cardiac output (CO) during conventional ventilation (0) and high-frequency oscillation (01.
111
,600
cv HFO
-
.400
UJI
t
,150 ,100 1
capnia
Normoxia Normacapnla
capnia (3min)
H ypoxia t-lypercapnia (3min)
Figure 3. Effect of ventilation with 12% 0215% CO2 (hypoxia/hypercapnia) upon pulmonary vascular resistance and systemic vascular resistance during conventional ventilation (CV> or high-frequency oscillation (HFO). PVR = pulmonary vascular resistance. SVR = systemic vascular resistance. *P <0.05 compared to ventilation with 02 enriched air (normoxia/normocapnia).
hypoxialhypercapnia during HFO was not significantly different (P = 0.07) from the response to the same stimulus during CV. The administration of 12% 0215% CO2 during periods of CV to neonatal piglets increased pulmonary arterial pressure 90 f 15% without significantly changing left atria1 pressure, cardiac output, or systemic arterial pressure (Figure 2). The calculated pulmonary vascular resistance increased 122 f 14% (Figure 3). Similar effects (P >0.05) were observed exposure to alveolar upon while HFO. HFO, hypoxia/hypercapnia ventilating with During pulmonary arterial pressure increased 72 f 15%. Pulmonary vascular resistance increased 78 f 23%. Changes in left atria1 pressure, cardiac output, and systemic arterial pressure were not significant.
112
HFO compared to CV did not alter arterial blood gases during either normoxia (pll 7.44 f 0.02, Po2 188 f 15 mm Hg, Pco2 35 f 1 mm Hg with CV versus pH 7.42 f 0.01, Pop 145 f 15 mm Hg, Pco2 33 f 2 mm Hg with HFO) or during hypoxic/hypercapnic ventilation (pH 7.30 f 0.02, Po2 40 f 3 mm Hg, Pco2 50 f 3 mm Hg with CV versus pH 7.31 f 0.02, Po2 44 f 4 nmtHg, Pco2 47 f 3 rmnHg with HFO). Plasma 6-keto-PGFl, and TXB2 concentrations were similar at about 300-400 pg/ml (Table I). Plasma PGE2 was not detectable
TABLE I. Pulmonary arterial (PA) and aortic (AO) blood concentrations of PG12 plus 6-keto-PGFl (PGI) and TXA2 plus TXB2 (TX) during ventilation with 92 enriched air (normoxia/normocapnia)and during ventilation with 12% 0215% CO2 (hypoxiafhypercapnia) in anesthetized neonatal piglets (N = 5).
PGI (pg/ml) A0 PA
TX (pg/ml) PA A0
Conventional Ventilation Normoxia/Normocapnia Hypoxia/Hypercapnia
310 f 43 448 f 61
291 f 41 264 f 72
324 f 97 399 f 67 395 f 115 314 f 65
High Frequency Oscillation Normoxia/Normocapnia Hypoxia/Hypercapnia
294 f 54 289 f 75 426 f 102 322 f 66
371 f 94 352 f 104 359 f 120 458 f 101
(<13 pg/ml) in these neonatal piglets. The method of ventilation (CV or HFO) had no effect upon plasma PG12 or thromboxane concentration. Net pulmonary PG12 production was not detectable (aorta concentration was less than pulmonary arterial 6-keto-PGFlo concentration) under any conditions used in the present experiments. DISCUSSION HFO has proven to be an effective mode of ventilation under a variety of circumstances (l-5). The present study was designed to evaluate how HFO affects prostanoid synthesis and hemodynamics during a period of alveolar hypoxia combined with mild hypercapnia. We hypothesized that HFO would augment pulmonary vascular proetacyclin synthesis and thus attenuate the pulmonary vasoconstrictor response to hypoxia/hypercapnia. However, we observed no significant effects of HFO on either pulmonary vascular PG metabolism or pulmonary hemodynamics. These findings suggest that, despite the very rapid ventilatory rate, the low tidal volumes
113
employed in HFO do not result in enough tissue distortion to alter arachidonic acid release and PG synthesis. There appear to be no significant hemodynamic effects of HFO, other than the absence of "respiratory variation" in the pressure and flow signals. We (13) and others (10,ll) have reported that alveolar hypoxia stimulates intrapulmonary synthesis of PGI2, a potent vasodilator, which may attenuate the vasoconstriction (13,141. In the present study, we could detect no difference in the net pulmonary production of PG12 or normoxia thromboxane during compared to cited hypoxia/hypercapnia. The experiments above, in which stimulation of pulmonary PG12 production by alveolar hypoxia was detected, used lungs perfused with physiological salt solution, allowing the entire pulmonary venous efflux to be collected. Further, the pulmonary arterial prostacyclin concentration was zero, permitting changes in pulmonary production to be detected pulmonary arterial readily. In present experiments, the radioimmunoassayable 6-keto-PGFlo was greater than pulmonary venous concentration indicating a net uptake of prostacyclin or 6-keto-PGFl, by the lung and obscuring any changes in intrapulmonary synthesis when only inflow and output concentrations were determined. Other investigators have reported no differences in either surfactant production or in lung morphology after periods of HFO (14,151. We detected no difference in prostanoid production or significant difference in the pulmonary response to combined alveolar hypoxia/hypercapnia dependent upon the mode of ventilation. We observed nothing that would contraindicate the use of HFO as an alternative mode of mechanically assisted ventilation. ACKNOWLEDGEMENTS technical assistance The authors acknowledge the excellent of Stephanie Adams and Mildred Jackson for their expert technical help and Rosalind Griffin for excellent secretarial assistance. Investigator of the American Dr. Leffler is an Established Heart Association with funds contributed in part by the Tennessee The research was supported by grants from the American Affiliate. Heart Association with funds contributed in part by the Tennessee Affiliate, The Tennessee Lung Association, the National Institutes of Health (AMO74051, and The University of Tennessee College of Medicine (Biomedical Research Support Grant). REFERENCES 1.
Bohn D, Miyasaka K, Marchak B, Thompson W, Froese A, Bryan Journal of A. Ventilation by high-frequency oscillation. Applied Physiology 48:710, 1980.
2.
Franz I, Westhammer J, Stark A. High-frequency ventilation in Adequate gas exchange premature infants with lung disease: at low tracheal pressure. Pediatrics 71:483, 1983.
114
3.
Sjostrand U. Summary of experimental and clinical features of high-frequency positive-pressure ventilation - HFPPV. Acta Anaesthesiologica Scandinavica 64:165, 1977.
4.
Slutsky A, Kamm R, Rossing T, Loring S, Lehr J, Shapiro A, Ingram R, Drazen J. Effects of frequency, tidal volume, and lung volume in CO2 elimination in dogs by high frequency (2-30 Hz), low tidal volume ventilation. Journal of Clinical Investigation 68:1475, 1981.
5.
Butler W, Bohn D, Bryan A, Froese A. frequency oscillation in humans. 59:577, 1980.
6.
Marchak B, Thompson W, Duffty P, Miyaki T, Bryan M, Froese A. Treatment of RDS by high-frequency oscillatory ventilation: A preliminary report. The Journal of Pediatrics 99:287, 1981.
7.
Piper P, Vane J. The release of prostaglandins from lung and other tissues. Annals of the New York Academy of Sciences 180:363, 1971.
8.
Said S. Pulmonary metabolism of prostaglandins and vasoactive peptides. Annual Review of Physiology 44:257, 1982.
9.
Green RS, Leffler CW. Hypoxia stimulates prostacyclin synthesis by neonatal lungs. Pediatric Research (in press).
10.
Voelkel N, Gerber J, McMurtry I, Nies A, Reeves J. Release of vasodilator prostaglandin, PG12, from isolated rat lung during vasoconstriction. Circulation Research 48:207, 1981.
11.
Hamasaki Y, Tai H, Said S. Hypoxia stimulates prostacyclin generation by dog lung -in vitro. Prostaglandins Leukotrienes and Medicine 8:311, 1982.
12.
Leffler C, Hessler J, Green R. Surgery increases fetal prostacyclin. Prostaglandins 24:387, 1982.
13.
Leffler C, Hessler J, Green R. The onset of breathing at birth stimulates pulmonary vascular prostacyclin synthesis. Pediatric Research (in press).
14.
Frantz I, Stark A, Davis J, Davies P, Kitzmiller T. Highfrequency ventilation does not affect pulmonary surfactant, liquid, or morphologic features in normal cats. American Review of Respiratory Diseases 126:909, 1982.
15.
Truog W, Standaert T, Murphy J, Palmer S, Woodrum D, Hodson W. Effect of high-frequency oscillation on gas exchange and pulmonary phospholipids in experimental hyaline membrane disease. American Review of Respiratory Diseases 127:585, 1983.
115
Ventilation of highAnesthesia and Analgesia