Neonatal Diaphragmatic Hernia: A Physiologic Challenge Albert W. Dibbins, MD, Portland,
Maine
Murdock, Burrington, and Sawyer [I] first reported that, in neonates with repaired diaphragmatic hernia, simultaneous measurements of Pa02 in radial artery and descending aorta demonstrated alveolar-radial gradients due to venous admixture (right to left shunting) across the foramen ovale and/or lung, and radial-aortic gradients due to venous admixture across the ductus arteriosus. These observations were confirmed by other investigators and extended by cardiac catheterization [2,3]. Elevated pulmonary artery pressures, right ventricular end-diastolic hypertension, elevated atria1 pressures, and left atria1 desaturation were described. Pulmonary angiography showed minimal flow through the unexpanded “hypoplastic” ipsilateral lung. On the basis of these studies it has been proposed that the majority of the right ventricular output is forced through the expanded contralateral lung. With a normal blood volume the unilateral pulmonary circulation becomes overdistended, elevating pulmonary artery, right ventricular end-diastolic, and right atria1 pressures. Changes in inspired oxygen concentration, hypoxemia, acidosis, increases in pulmonary vascular volume, or increases in pulmonary transmural pressure may precipitate pulmonary arteriolar vasoconstriction, causing right to left shunting within the lung, across the foramen ovale, or across the ductus arteriosus. The ductus arteriosus serves as a “vent” to the pulmonary circulation, but constriction may precipitate diastolic hypertension, whereas wide patency may decrease pulmonary blood flow and shunt desaturated blood into the systemic circulation to produce hypoxemic tissue acidosis. Survival of the infant depends on a balance between pulmonary arterial and ductal tone and the ability of the right ventricle to maintain output with an increased workload until the ipsilateral lung expands. Ligation of the ductus arteriosus to
From the Department of Surgery, Maine Medical Center, Portland, Maine. Reprint requests should be addressed to Albert N. Dibbins. MD, Department of Surgery, Maine Medical Center, Portland, Maine 04102. Presented at the Fifty-Sixth Annual Meeting of the New England Surgical Society, Portsmouth, New Hampshire, September 25-27, 1975.
408
decrease shunting has been unsuccessful [2] and the use of pulmonary arterial vasodilators has met with limited success [3]. In two recent patients methylprednisolone and chlorpromazine have been used to decrease pulmonary vascular amine
resistance
to maintain
in combination
cardiac
output.
with dop-
One child
has
died, the other has survived.
Material and Methods Both infants were nasotrachially intubated on controlled respirations with a Baby Bird ventilator. Fractional inspired oxygen concentrations were regulated by an attached oxygen controller. Arterial samples were obtained from indwelling right radill and abdominal aortic or dorsalis pedis catheters. Determinations of pH, PaC02, COa, and Pa02 were performed on an Instrumentation Laboratories pH gas analyzer. Right to left shunt of 20 per cent was considered “normal” for the newborn period. If Pa02 in the radial sample was below that predicted for 20 per cent shunt determined by a shunt graph, preductal shunting was said to be present. If Pa02 in the radial sample was 20 mm Hg greater than in the simultaneous aortic sample, ductal shunting was considered to be present. Arterial pressure was measured by transducers attached to the radial line displayed on a Hewlett-Packard monitor both as a digital readout and as an arterial pressure wave. Case I. BBL, a 1 hour old male, was resuscitated and intubated in the delivery room. A right sided posterolatera1 diaphragmatic hernia was repaired at 2 hours of age. Postoperatively paired radial and aortic PaOzs were 40 to 45 on 100 per cent oxygen. Methylprednisolone and chlorpromazine did not increase PaOa. A dopamine drip was begun, increasing blood pressure from 45122 to 77154 with simultaneous increases in radial and aortic PaOns to 60. Although this improvement. was maintained for several hours, he died with progressive metabolic acidosis. At postmortem examination the ductus arteriosus was widely patent and the foramen ovale was covered by a loosely attached thin transparent membrane. Case II. LL, an infant girl, had a left sided Bochdalek hernia repaired at 4 hours of age. Pa02 was 110 on 75 per cent oxygen after repair; 2 hours postoperatively, the Pa02 abruptly decreased to 33 in the radial sample. Responding to 100 per cent oxygen, digitalization, and methylprednisolone, she had a large ductal shunt, with a
The American Journal of Surgery
Neonatal Diaphragmatic Hernia
radial Pa02 of 225 and an aortic Pa02 of 71 on 60 per cent oxygen. Blood pressure and radial PO2 gradually declined after several hours, indicating increased pulmonary vascular resistance and myocardial decompensation. Dopamine drip was begun and pressure was restored, but after 5 hours increasing preductal shunt again became evident. Chlorpromazine was added to the drip, thus increasing preductal Pa02 as pulmonary vascular resistance declined. Five hours later Pa02 again declined but responded to positive end expiratory pressure without a decrease in blood pressure. Ipsilateral lung expansion began at 50 to 60 hours postoperatively together with ductal closure. She was weaned from the chlorpromazine on the sixth postoperative day and from dopamine on the tenth.
Comments Pulmonary vasoconstriction in response to hypoxemia is a striking feature of the neonatal period and is accentuated by acidosis [4]. At a pH of 7.35 significant increases in pulmonary vascular resistance occur with a Pa02 of 50. At lower pH increased resistance occurs with higher PaOas. The response of the ductus arteriosus to oxygen tension is opposite that of the pulmonary arteriolar bed. Constriction begins in lambs at a Pa02 of 50 and is complete at a Pa02 of 200 [5]. Pulmonary arterioles and the ductus constrict in response to norepinephrine, the major catecholamine of the neonate. Histochemical studies of the ductal wall show large numbers of adrenergic nerve terminals containing norepinephrine in the media; epinephrine and dopamine are not present. Alpha blockade prevents the catechol response but does not affect the response to POs. Ideal pharmacologic treatment of the neonate with diaphragmatic hernia would be to prevent pulmonary vasoconstriction due to catecholamines without producing systemic hypotension. There is experimental evidence in young animals to suggest that steroids decrease the sensitivity of pulmonary arterioles to norepinephrine, and methylprenisolone was chosen for this reason. Chlorpromazine in doses of 1 mg/kg or less has been shown to decrease right ventricular work and to decrease pulmonary vascular resistance to a greater degree than systemic vascular resistance [6,8]. At these doses chlorpromazine also increases cardiac output [ 7,8], and the decrease in resistance is due to a decrease in pulmonary artery pressure as a result of local alpha blockade in both the arteriolar walls and myocardium. No studies of chlorpromazine’s effects on the ductus have been reported.
Voklm~ 131, April 1976
Despite alpha blockade of the pulmonary circulation, constriction in response to hypoxemia, acidosis, and increased transmural pressure persists, and right ventricular overload may result. Dopamine, an endogenous catecholamine, appears to be a particularly useful drug under these circumstances, At doses of 10 bg/kg/min or less, dopamine increases myocardial contractility by direct beta stimulation. Skeletal blood flow is decreased and renal and mesenteric blood flow are increased [9] by stimulation of dopaminergic receptors. The increases in renal flow are accompanied by increased sodium excretion. In studies of adults [IO] pulmonary wedge pressure, pulmonary vascular resistance, and mean pulmonary pressure were not modified in this dose range. Higher dosages cause alpha adrenergic vasoconstriction, and personal observation indicates that this effect is exaggerated in the neonate unless alpha blockade is used. In the two patients reported on, the use of dopamine to support the myocardium was accompanied by increases in systemic pressure and increases in arterial oxygen tensions presumably due to increases in cardiac output. Isoproterenol used under the same circumstances for its beta properties has failed previously [3] for reasons that are not understood. The drug combination appears to offer advantages for hemodynamic support in the neonatal period when the ability to revert to a fetal circulation persists.
References 1. MurdockAl, BurringtonJB, Sawyer PR: Alveolar to arterial oxygen tension difference and venous ad mixture in newly born infants with congenital herniation through the foramen of Bochdalek. BiolNeonate 17: 161, 1971. 2. Collins D: Paper presented at American Pediatric Surgical Association meeting, New Orleans, Louisiana, April 1974. 3. Dibbins AW, Wiener ES: Mortality from neonatal diaphragmatic hernia. J Pediah Surg 9: 653, 1974. 4. Rudolph AM, Yuan S: Response of the pulmonary vasculature to hypoxia and H+ ion concentration change. J C/in Invest 45: 399, 1966. 5. Heymann MA, Rudolph AM: Control of the ductus arteriosus. Physiol Rev 55: 62, 1975. 6. Maxwell GM, et al: Hemodynamic effects of chlorpromazine including studies of cardiac work and coronary blood flow. Anesthesiol 19: 64, 1956. 7. Goldberg BJ, Linde LM, Wolfe RR. et al: The effects of meperedine, promethazine, and chlorpromazine on pulmonary and systemic circulation. Am HeartJ 77: 214, 1969. 8. Bormann JB, et al: The beneficial effects of chlorpromazine on pulmonary hemodynamics after cardio-pulmonary bypass. Ann Thorac Surg 11: 570. 197 1. 9. Goldberg LI: Dopamine-clinical uses of an endogenous catecholamine. N Engl J Med 291: 707. 1974. 10. Beregovich J: Dose related hemodynamic and renal effects of dopamine in congestive heart failure. Am Heart J 87: 550, 1974.
409
Dibbins
Discussion Judah Folkman (Boston, MA): Doctor Dibbins made the point quite clearly that if the lung fails to develop in the fetus and the intestine keeps the lung compressed, then these lungs do not develop properly and their vasculature may also be abnormal. He has focused our attention on the pulmonary vasculature and has shown that lowering the pulmonary vascular resistance may help reduce the high mortality of these babies. At the other end of the spectrum is the newborn baby whose lung does develop completely but whose diaphragm is still open at birth. The intestine may enter tbe chest just before or after birth and compress the lung for weeks or years without symptoms. Will such a lung reexpand normally after operative relocation of the intestine into the abdomen? I saw a ten year old girl recently who provides an answer. She was always perfectly healthy. While at summer camp, she developed midabdominal pain for two days followed by vomiting, high fever, and then left shoulder pain. At another hospital, she was thought to have pneumonia, but the diagnosis soon became left diaphragmatic hernia. (Slide) Barium studies showed that all of the intestine was in the left chest; only the left colon was in the abdomen. She was referred to us and at surgery I found that the entire abdominal cavity was tiny and infantile. All of the intestine was in the chest; it had never
410
been in the abdomen. After the intestine was brought down through a large Bochdalek hernia in the left diaphragm, we found that there was a mass in the chest, which turned out to be a perforated appendix with an abscess cavity in the apex of the chest, up under the pleura. In the next slide you see a chest film in the recovery room; the lung is already 99 per cent expanded. The next slide shows her two weeks after operation, during a visit to the office. There are two lessons from this case. The first is if the lung has reached normal development, it can be compressed and collapsed totally for ten years or more (as long as obstruction of the bronchial tree is not the cause of collapse), yet it will reexpand normally. The second lesson is that appendicitis almost always begins with periumbilical pain, referred to the tenth thoracic dermatome no matter where the appendix is. Even if the appendix is in the apex of the chest, its first stretch receptor response is to refer pain to the periumbilical region. Vomiting may follow. Then, depending on where inflammatory fluids from the appendix accumulate, this determines where the pain will shift. If this accumulation is in the right lower quadrant, the pain may shift there; if the accumulation is in the retroperitoneal area, there may be no shift; if the appendix is in the chest, the pain shifts there. I think this case certainly documents the mechanism of pain patterns in appendicitis.
The American Journal of Surgery
Maine
Murdock, Burrington, and Sawyer [I] first reported that, in neonates with repaired diaphragmatic hernia, simultaneous measurements of Pa02 in radial artery and descending aorta demonstrated alveolar-radial gradients due to venous admixture (right to left shunting) across the foramen ovale and/or lung, and radial-aortic gradients due to venous admixture across the ductus arteriosus. These observations were confirmed by other investigators and extended by cardiac catheterization [2,3]. Elevated pulmonary artery pressures, right ventricular end-diastolic hypertension, elevated atria1 pressures, and left atria1 desaturation were described. Pulmonary angiography showed minimal flow through the unexpanded “hypoplastic” ipsilateral lung. On the basis of these studies it has been proposed that the majority of the right ventricular output is forced through the expanded contralateral lung. With a normal blood volume the unilateral pulmonary circulation becomes overdistended, elevating pulmonary artery, right ventricular end-diastolic, and right atria1 pressures. Changes in inspired oxygen concentration, hypoxemia, acidosis, increases in pulmonary vascular volume, or increases in pulmonary transmural pressure may precipitate pulmonary arteriolar vasoconstriction, causing right to left shunting within the lung, across the foramen ovale, or across the ductus arteriosus. The ductus arteriosus serves as a “vent” to the pulmonary circulation, but constriction may precipitate diastolic hypertension, whereas wide patency may decrease pulmonary blood flow and shunt desaturated blood into the systemic circulation to produce hypoxemic tissue acidosis. Survival of the infant depends on a balance between pulmonary arterial and ductal tone and the ability of the right ventricle to maintain output with an increased workload until the ipsilateral lung expands. Ligation of the ductus arteriosus to
From the Department of Surgery, Maine Medical Center, Portland, Maine. Reprint requests should be addressed to Albert N. Dibbins. MD, Department of Surgery, Maine Medical Center, Portland, Maine 04102. Presented at the Fifty-Sixth Annual Meeting of the New England Surgical Society, Portsmouth, New Hampshire, September 25-27, 1975.
408
decrease shunting has been unsuccessful [2] and the use of pulmonary arterial vasodilators has met with limited success [3]. In two recent patients methylprednisolone and chlorpromazine have been used to decrease pulmonary vascular amine
resistance
to maintain
in combination
cardiac
output.
with dop-
One child
has
died, the other has survived.
Material and Methods Both infants were nasotrachially intubated on controlled respirations with a Baby Bird ventilator. Fractional inspired oxygen concentrations were regulated by an attached oxygen controller. Arterial samples were obtained from indwelling right radill and abdominal aortic or dorsalis pedis catheters. Determinations of pH, PaC02, COa, and Pa02 were performed on an Instrumentation Laboratories pH gas analyzer. Right to left shunt of 20 per cent was considered “normal” for the newborn period. If Pa02 in the radial sample was below that predicted for 20 per cent shunt determined by a shunt graph, preductal shunting was said to be present. If Pa02 in the radial sample was 20 mm Hg greater than in the simultaneous aortic sample, ductal shunting was considered to be present. Arterial pressure was measured by transducers attached to the radial line displayed on a Hewlett-Packard monitor both as a digital readout and as an arterial pressure wave. Case I. BBL, a 1 hour old male, was resuscitated and intubated in the delivery room. A right sided posterolatera1 diaphragmatic hernia was repaired at 2 hours of age. Postoperatively paired radial and aortic PaOzs were 40 to 45 on 100 per cent oxygen. Methylprednisolone and chlorpromazine did not increase PaOa. A dopamine drip was begun, increasing blood pressure from 45122 to 77154 with simultaneous increases in radial and aortic PaOns to 60. Although this improvement. was maintained for several hours, he died with progressive metabolic acidosis. At postmortem examination the ductus arteriosus was widely patent and the foramen ovale was covered by a loosely attached thin transparent membrane. Case II. LL, an infant girl, had a left sided Bochdalek hernia repaired at 4 hours of age. Pa02 was 110 on 75 per cent oxygen after repair; 2 hours postoperatively, the Pa02 abruptly decreased to 33 in the radial sample. Responding to 100 per cent oxygen, digitalization, and methylprednisolone, she had a large ductal shunt, with a
The American Journal of Surgery
Neonatal Diaphragmatic Hernia
radial Pa02 of 225 and an aortic Pa02 of 71 on 60 per cent oxygen. Blood pressure and radial PO2 gradually declined after several hours, indicating increased pulmonary vascular resistance and myocardial decompensation. Dopamine drip was begun and pressure was restored, but after 5 hours increasing preductal shunt again became evident. Chlorpromazine was added to the drip, thus increasing preductal Pa02 as pulmonary vascular resistance declined. Five hours later Pa02 again declined but responded to positive end expiratory pressure without a decrease in blood pressure. Ipsilateral lung expansion began at 50 to 60 hours postoperatively together with ductal closure. She was weaned from the chlorpromazine on the sixth postoperative day and from dopamine on the tenth.
Comments Pulmonary vasoconstriction in response to hypoxemia is a striking feature of the neonatal period and is accentuated by acidosis [4]. At a pH of 7.35 significant increases in pulmonary vascular resistance occur with a Pa02 of 50. At lower pH increased resistance occurs with higher PaOas. The response of the ductus arteriosus to oxygen tension is opposite that of the pulmonary arteriolar bed. Constriction begins in lambs at a Pa02 of 50 and is complete at a Pa02 of 200 [5]. Pulmonary arterioles and the ductus constrict in response to norepinephrine, the major catecholamine of the neonate. Histochemical studies of the ductal wall show large numbers of adrenergic nerve terminals containing norepinephrine in the media; epinephrine and dopamine are not present. Alpha blockade prevents the catechol response but does not affect the response to POs. Ideal pharmacologic treatment of the neonate with diaphragmatic hernia would be to prevent pulmonary vasoconstriction due to catecholamines without producing systemic hypotension. There is experimental evidence in young animals to suggest that steroids decrease the sensitivity of pulmonary arterioles to norepinephrine, and methylprenisolone was chosen for this reason. Chlorpromazine in doses of 1 mg/kg or less has been shown to decrease right ventricular work and to decrease pulmonary vascular resistance to a greater degree than systemic vascular resistance [6,8]. At these doses chlorpromazine also increases cardiac output [ 7,8], and the decrease in resistance is due to a decrease in pulmonary artery pressure as a result of local alpha blockade in both the arteriolar walls and myocardium. No studies of chlorpromazine’s effects on the ductus have been reported.
Voklm~ 131, April 1976
Despite alpha blockade of the pulmonary circulation, constriction in response to hypoxemia, acidosis, and increased transmural pressure persists, and right ventricular overload may result. Dopamine, an endogenous catecholamine, appears to be a particularly useful drug under these circumstances, At doses of 10 bg/kg/min or less, dopamine increases myocardial contractility by direct beta stimulation. Skeletal blood flow is decreased and renal and mesenteric blood flow are increased [9] by stimulation of dopaminergic receptors. The increases in renal flow are accompanied by increased sodium excretion. In studies of adults [IO] pulmonary wedge pressure, pulmonary vascular resistance, and mean pulmonary pressure were not modified in this dose range. Higher dosages cause alpha adrenergic vasoconstriction, and personal observation indicates that this effect is exaggerated in the neonate unless alpha blockade is used. In the two patients reported on, the use of dopamine to support the myocardium was accompanied by increases in systemic pressure and increases in arterial oxygen tensions presumably due to increases in cardiac output. Isoproterenol used under the same circumstances for its beta properties has failed previously [3] for reasons that are not understood. The drug combination appears to offer advantages for hemodynamic support in the neonatal period when the ability to revert to a fetal circulation persists.
References 1. MurdockAl, BurringtonJB, Sawyer PR: Alveolar to arterial oxygen tension difference and venous ad mixture in newly born infants with congenital herniation through the foramen of Bochdalek. BiolNeonate 17: 161, 1971. 2. Collins D: Paper presented at American Pediatric Surgical Association meeting, New Orleans, Louisiana, April 1974. 3. Dibbins AW, Wiener ES: Mortality from neonatal diaphragmatic hernia. J Pediah Surg 9: 653, 1974. 4. Rudolph AM, Yuan S: Response of the pulmonary vasculature to hypoxia and H+ ion concentration change. J C/in Invest 45: 399, 1966. 5. Heymann MA, Rudolph AM: Control of the ductus arteriosus. Physiol Rev 55: 62, 1975. 6. Maxwell GM, et al: Hemodynamic effects of chlorpromazine including studies of cardiac work and coronary blood flow. Anesthesiol 19: 64, 1956. 7. Goldberg BJ, Linde LM, Wolfe RR. et al: The effects of meperedine, promethazine, and chlorpromazine on pulmonary and systemic circulation. Am HeartJ 77: 214, 1969. 8. Bormann JB, et al: The beneficial effects of chlorpromazine on pulmonary hemodynamics after cardio-pulmonary bypass. Ann Thorac Surg 11: 570. 197 1. 9. Goldberg LI: Dopamine-clinical uses of an endogenous catecholamine. N Engl J Med 291: 707. 1974. 10. Beregovich J: Dose related hemodynamic and renal effects of dopamine in congestive heart failure. Am Heart J 87: 550, 1974.
409
Dibbins
Discussion Judah Folkman (Boston, MA): Doctor Dibbins made the point quite clearly that if the lung fails to develop in the fetus and the intestine keeps the lung compressed, then these lungs do not develop properly and their vasculature may also be abnormal. He has focused our attention on the pulmonary vasculature and has shown that lowering the pulmonary vascular resistance may help reduce the high mortality of these babies. At the other end of the spectrum is the newborn baby whose lung does develop completely but whose diaphragm is still open at birth. The intestine may enter tbe chest just before or after birth and compress the lung for weeks or years without symptoms. Will such a lung reexpand normally after operative relocation of the intestine into the abdomen? I saw a ten year old girl recently who provides an answer. She was always perfectly healthy. While at summer camp, she developed midabdominal pain for two days followed by vomiting, high fever, and then left shoulder pain. At another hospital, she was thought to have pneumonia, but the diagnosis soon became left diaphragmatic hernia. (Slide) Barium studies showed that all of the intestine was in the left chest; only the left colon was in the abdomen. She was referred to us and at surgery I found that the entire abdominal cavity was tiny and infantile. All of the intestine was in the chest; it had never
410
been in the abdomen. After the intestine was brought down through a large Bochdalek hernia in the left diaphragm, we found that there was a mass in the chest, which turned out to be a perforated appendix with an abscess cavity in the apex of the chest, up under the pleura. In the next slide you see a chest film in the recovery room; the lung is already 99 per cent expanded. The next slide shows her two weeks after operation, during a visit to the office. There are two lessons from this case. The first is if the lung has reached normal development, it can be compressed and collapsed totally for ten years or more (as long as obstruction of the bronchial tree is not the cause of collapse), yet it will reexpand normally. The second lesson is that appendicitis almost always begins with periumbilical pain, referred to the tenth thoracic dermatome no matter where the appendix is. Even if the appendix is in the apex of the chest, its first stretch receptor response is to refer pain to the periumbilical region. Vomiting may follow. Then, depending on where inflammatory fluids from the appendix accumulate, this determines where the pain will shift. If this accumulation is in the right lower quadrant, the pain may shift there; if the accumulation is in the retroperitoneal area, there may be no shift; if the appendix is in the chest, the pain shifts there. I think this case certainly documents the mechanism of pain patterns in appendicitis.
The American Journal of Surgery
