Eur J Cardio-thorac

Surg (1991) 5:628-634

(0 SpringG-Verlag

199 1

Pulmonary hypertensive crises following surgery for congenital heart defects in young children R.A. Hopkins, C. Bull, S. G. Haworth, M.R. de Leval, and J. Stark The Thoracic Unit, The Hospital for Sick Children, London,

England, UK

Abstract. In this clinical study, 20 high risk infants and neonates were monitored to identify and characterize pulmonary hypertensive crises following surgery for congenital cardiac defects. Monitoring included right ventricular or pulmonary artery pressure catheters and transcutaneous oximetry. Eleven patients also had continuous analog recording of hemodynamic data so that antecedents of crises and the sequence of events following treatment could be reconstructed. Eleven of the 20 patients had one or more crises. Six of these ultimately died whereas 5 patients survived with aggressive vasodilator therapy. Four patients without crises but with episodic pulmonary hypertension benefitted from pulmonary vasodilator therapy to ease weaning from ventilatory support. Typically, each crisis was associated with a stress event. Crises were difficult to ablate if not rapidly treated and multiple crises would often cluster following an initial event. High dose narcotic (fentanyl) analgesia was found to be important in the postoperative management. Tolazoline and oxygen were the most consistently useful vasodilators, but isoproterenol and nitrates also played a role. Five of the children who died were examined post mortem: histologically, there was increased pulmonary arterial muscularization in 2, in none were there changes of fixed pulmonary vascular disease. The postoperative management must be individualized on the basis of monitored responses of pulmonary circulation. [Eur J Cardio-thorac Surg (1991) 5:62?3-6341 Key words: Pulmonary hypertension - Congenital heart disease - Neonatal cardiac surgery - Pulmonary reactivity - Postoperative cardiac surgery

Children with congenital cardiac defects associated with high pulmonary artery pressure may die despite surgery [24, 531. Postoperative mortality has been attributed to acute rises in pulmonary artery pressure and resistance. Though such pulmonary hypertensive crises have been sporadically described, their etiology is uncertain and therapy remains empiric [7, 12, 24, 531. This clinical observational study was designed to identify the variables required to monitor crises, to note the initiating events, and to determine the hemodynamic features associated with this problem in infants at risk following surgery for congenital heart disease.

Material and methods Definitions An acute pulmonary

a paroxysmal

hypertensive crisis was defined in this study as event in which pulmonary arterial systolic pressure

Received for publication: August 12, 1991 Accepted for publication: August 29, 1991

vascular

rose to equal or exceed systemic levels followed by a rapid fall in systemic pressure. A minor pulmonary

in pulmonary but without a the pulmonary but the latter

hypertensive event was defined as an acute rise arterial pressure to more than 80% of systemic levels fall in systemic pressure. Peak and mean pressures in artery could approach or even exceed aortic pressure did not fall.

Patients Only patients thought to be at risk for postoperative pulmonary hypertensive problems were considered for monitoring of transthoracic pulmonary artery pressure [24, 42, 531. Cardiac defects thought to predispose to a reactive pulmonary vasculature included three main groups: firstly, complex transposition, truncus arteriosus, and atrioventricular septal defect treated in infancy even when pulmonary vascular resistance estimated at preoperative cardiac catheterization was low [19]. Secondly, children with more straightforward anatomy, e.g., ventricular septal defect when elevation of the pulmonary vascular resistance had been documented at cardiac catheterization, and thirdly, neonates following open complex heart surgery [16, 181. During the 9 months of study, 144 patients underwent open heart surgery in our unit of which 32 by diagnosis

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Therapy protocol

Table 1. Patient population Diagnosis

Age at operation

Crises

Minor events

Survival

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

13m 14m 2m 30m llm 23 m 6m 8m 14m 3d 40d 2m 12m 14m 2m 14m 4m Id 5m 4d

~ ~ ~ 5 1 10 8 2 17 3 1 5

_ _ _ _ _ 14 2 5 2 20 3 25 10 14 43 _ _ _

yes yes yes yes yes yes yes yes yes yes yes yes yes yes died day died day died day died day diedday died day

AVSD (Down’s) VSD (PHT) VSD (PHT) DORV (PHT) VSD (PHT) AVSD (PDA, Down’s) VSD (PHT) AVSD (Down’s) AVSD (PDA, Down’s) TAPVD TAPVD TGA (VSD) VSD (PHT) AVSD (Down’s) TGA (PHT) AVSD TAPVD TAPVD Truncus arteriosus Interrupted aortic arch

++t+ 6

++++ 75

Prophylactic measures. Early postoperatively, ventilation was maintained with levels of inspired oxygen (FIO,) sufficient to maintain a transcutaneous oxygen measurement (P,O,) above 100 mmHg (usually an arterial p0, above 120 mmHg) and arterial pC0, around 30 mmHg. All patients were paralyzed with pancuronium for the first 12 h and fentanyl analgesia administered by continuous infusion at 4-8 mcg/kg per hour (occasionally as high as 25 mcg/kg per hour for short periods). Dopamine was the most generally used inotropic agent though doses higher than 5 mcg/kg per minute were avoided by adding isoproterenol when necessary [14, 32, 501. If no hypertensive events occurred and pulmonary artery pressure was below 0.75 of systemic, paralysis was discontinued and the patient weaned from ventilation. If pulmonary artery pressure rose gradually, ventilator weaning was delayed, sedation carefully maintained, and a nitrate vasodilator (nitroprusside, nitroglycerin) commenced.

9 0 0 1 7 6

PHT = preoperative catheterization defined significantly elevated pulmonary vascular resistance > 4 units; m = months; d = days; AVSD = atrioventricular septal defect; PDA = persistent ductus arteriosus; VSD = ventricular septal defect; DORV = double outlet right ventricle; TAPVD = total anomalous venous drainage; TGA = transposition of great arteries; + + + + = too many episodes to count

could have been considered as at risk. Of these, 20 were monitored per protocol. There were 3 neonates (mean age 3 days) and 17 other infants and young children aged 40 days to 30 months whose diagnoses and operations are listed in Table 1.

Monitoring Patients were monitored postoperatively with right ventricular or pulmonary artery pressure catheters and transcutaneous oximetry in addition to the usual hemodynamic monitoring of right atria1 and systemic arterial pressure. Ten right ventricular and 10 pulmonary arterial lines were used. These were placed percutaneously via the internal jugular vein in four patients’, transthoracically via the right atrium in 12 and through the right ventricular myocardium in 4 patients. One patient’s line was removed on the 1st postoperative day but a flow-guided balloon catheter’ was passed into the pulmonary artery 1 day later for suspected and later proven pulmonary hypertensive crises. Pressures were obtained using fluid-tilled catheters and quartz 3 pressure transducers with a Hewlett-Packard monitoring system. Eleven patients had continuous analog recording of hemodynamic data (Hewlett-Packard 8 channel recorder and a Grass model 70 polygraph) so that the antecedents of crises and the sequence of events following treatment could be reconstructed, if necessary, on a beat to beat basis. The frequency of occurrence of hypertensive events and their response to treatment could thus be determined. Rectal and toe temperatures were also recorded.

i Radioplast, Uppsala ’ Swan-Ganz 3 Hewlett-Packard

Management of minor events. Acute pulmonary hypertension, even without a fall in systemic pressure, prompted hand ventilation with 100% oxygen and increased analgesia. A vasodilator was then infused (nitroglycerin or tolazoline). Isoproterenol was begun alone or gradually substituted for part or all of dopamine inotropic support. Management

of hypertensive crises. When the systemic arterial pressure fell, additional measures were urgently instituted: first pure oxygen hyperventilation by hand and complete sedation were established. Sodium bicarbonate (1 mEq/kg i.v.) was given as a bolus and isoproterenol begun (if not already started). Tolazoline (1 mg/kg over l-2 min) was administered intravenously along with a dose of calcium chloride (10 mg/kg) which helped counteract the immediate systemic hypotension seen with the drug (maximum of four doses). If matters improved, tolazoline was administered as a constant intravenous infusion (1 mg/kg per hour to a maximum of 4 mg/kg per hour); if not, other drugs were tried (prostacycline: 20-50 nanograms/kg per minute, nitroglycerin: 0.5-2.0 mcg/kg per minute, and finally phenoxybenzamine: 2 mg/kg bolus). If pulmonary hypertensive crises occurred, heavy sedation, paralysis and hyperventilation were maintained for at least 24 h and often longer. If an effective pulmonary vasodilator regimen had been found for the patient, ventilatory support was weaned before the drugs were reduced. Though our treatment protocol was fairly standardized, the purpose of this study was to observe the events rather than to test a specific therapeutic modality, drug, or sequence of interventions. Patient management was not restricted to a precise protocol during these life threatening episodes.

Histology Autopsies were performed on all but 1 of the patients who died. In each case, the intracardiac repair was intact; 1 neonate had a significant intracerebral hemorrhage. The lungs were sectioned for quantitative morphometric studies of the pulmonary arteries by techniques previously described [15].

Results

Of the 20 patients, 11 developed significant major pulmonary hypertensive crises. Six of these patients died, 5 as a direct result of pulmonary hypertension, and 1 of intracerebral hemorrhage but with pulmonary hypertension as a major contributing factor. Nearly all patients having crises also demonstrated minor events. Four patients who had only minor events were treated with va-

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sodilator to ease ventilatory weaning and survived. The 5 patients without pulmonary hypertensive episodes also survived and there were no complications attributable to the monitoring or to specific therapeutic interventions.

Patients with pulmonary hypertensive crises Of the 11 patients having crises (10-20, Table I), the initial crisis occurred on the day of surgery in 5 patients, on the 1st postoperative day in 3, on the 2nd day in 2, and on the 5th day in 1 patient. Typically, each initial crisis was associated with a stress event. In 6 patients, the initiating stress appeared to have been inadequate analgesia or paralysis (3 inadvertent and 3 during planned, gradual weaning of ventilatory support or endotracheal suctioning). Other initiating events observed where hypovolemic systemic hypotension, atelectasis with hypoxia, systemic hypotension induced by a nodal bradycardia, and abrupt cessation of tolazoline infusion. Crises were difficult to ablate if not rapidly treated and multiple crises would often cluster following an initial event. Subsequent crises did not always have identifiable initiating events. Minor events could presage or occur in the aftermath of a crisis. Two patients died within an hour of surgery, 1 during his first crisis without responding to any therapy. The second patient had three crises and died of the third event despite an initial positive response to tolazoline (Fig. 1). The 5 survivors of multiple major crises had a total of 26 crises and 72 minor events. These patients required tolazoline (N = 14) and prostacycline (N = 1) infusions for ventilator weaning and extubation which was achieved on the 4th postoperative day in 1 patient, the 5th day in 2, and the 8th day in 2 patients. All had received low dose dopamine, 4 isoproterenol, 3 nitroprusside and 2 nitroglycerin. While loss of response to one pharmacological vasodilator (e.g., tolazoline) did not necessarily preclude a subsequent response to a second added vasodilator (e.g., prostacycline), all patients who died were eventually refractory even to hand ventilation by the time of their lethal crisis. Conversely, a good response to oxygen and hyperventilation seemed to correlate with responsiveness to pharmacologic vasodilation. Hand ventilation was always superior to any ventilator modality for hyperventilation during an episode.

Fig. 1. This is the second of three acute crises in a lCmonth-old Down’s child following repair of AV septal defect with PDA. The third episode followed this one by 10 min and was fatal. Note the absence of PtEO, (TCOM) response to hyperventilation, the concomitant rise in right ventricular (RV) pressure with fall in P,,O, and the subsequent systemic hypotension. The tolazoline bolus effected pulmonary arterial vasodilation with subsequent rise in arterial blood pressure. Note also in this patient that the best P,cO, = 50 Torr with inspired oxygen= 100% and simultaneous PaO, = 55 Torr. Blunted oxygenation is typical for clustering episodes. The RV diastolic pressure elevation is characteristic of a crisis

ECG

nxu 76

Patients with multiple minor events All 4 patients having only multiple minor events survived. Identitiable stimuli included fever, endotracheal suctioning, and episodes of agitation during weaning from ventilator or analgesia. Three of these patients responded to tolazoline infusion and 1 to nitroglycerin. Two patient also received isoproterenol. With pharmacological vasodilator therapy, pancuronium paralysis could usually be discontinued. All minor events reponded to hand ventilation with 100% oxygen which reversed the rise in pulmonary arterial/systemic pressure ratio and produced no compromise in systemic cardiac output (Fig. 2).

Fig. 2. Response of minor pulmonary hypertensive event to hand hyperventilation with 100% oxygen in patient with transposition great arteries and VSD following arterial switch operation. During this minor pulmonary hypertensive event, the PA pressure had gradually risen over 3 min to 60/22 (B) mmHg associated with decline in P,,O,to 45 Torr. The aortic pressure had slowly declined from 70/50 to 64/47 mmHg (P,,/P,=O.9). Note the response to hand hyperventilation in PtsO, and drop in PA pressure thereafter. The aortic pressure rise was a bit of an overshoot and settled a few minutes later to 70/48 mmHg (P,/P, = 0.6). This patient had a total of 10 crises and 25 minor events and received tolazoline, isoproterenol, nitroglycerin, and fentanyl infusions which ultimately ablated these episodes and allowed extubation. (PA = pulmonary artery; TCOM = Transcutaneous oximeter)

631

Transcutaneous oximetry demonstrated falls in measured oxygen concentration either shortly before (seconds to 2 min) or concomitant with the rise in PA or RV pressures, improving as the pressure changes reversed. A pattern of recurrent minor events sometimes became established. One patient had an atrioventricular septal defect, persistent ductus arteriosus, Down’s syndrome, and an estimated pulmonary vascular resistance of 9.9 Wood units/M’ in air preoperatively (dropping to 2.2 Wood units/M’ in oxygen). His pulmonary arterial bed remained “hyper-reactive” postoperatively with sudden elevation of systolic PA pressure from 40% to 90% of systemic levels. These events always responded to 100% oxygen but would recur with attempts to reduce FIO,. After 48 h of tolazoline infusion, P,,O, spontaneously improved and he was weaned from the ventilator with a stable pulmonary artery pressure. Histology

At autopsy, pulmonary arterial muscularity was increased in 2 patients (17 and 19, Fig. 3). Muscle extended into more peripheral arteries than in normals and mean percentage medial thickness was increased in arteries 50- 100 u in diameter to 36% and 30%) respectively (normal 7.4% +2.5% P~0.01) [15]. In the 2 neonates (18 and 20), mean percentage arterial medial thickness was similar to that of normal children, being 27% and 23%, respectively, (normal 24.9% + 10.9O/). Intimal proliferation was not seen. Thus all children had pulmonary vascular changes which could be classified as clearly reversible.

Discussion Pulmonary hypertensive crises are a significant problem in certain young children undergoing surgery for congenital heart disease [53]. Despite the aggressive approach described in this report, eventual mortality was high whenever major crises occurred. This is similar to other studies, for example that of Jones et al. who reported the use of tolazoline postoperatively [24]. Though acute pulmonary vasoconstrictive episodes were often reversed, 7 of their 11 patients who had acute pulmonary hypertensive events ultimately died. There are several limitations to a study such as this: it was an observational study performed in the context of current management techniques rather than a trial of a particular protocol. Thus it was impossible to know how many minor events were prevented from progressing to crises since there was no randomization to non-therapy (which would be unethical). In the same way, it is difficult to know how many children with definite crises lived as a consequence of therapy though it seems likely that 5 were saved by appropriate use of pulmonary vasodilator. Four patients with minor events had a smoother ventilator weaning by resorting to pharmacological vasodilation. Endotracheal suctioning was a particularly strong stimulus which prompted pretreatment with oxygen hyperventilation and narcotic boluses. The concept of chronic postoperative anesthesia has demonstrated efticacy in the control of pulmonary hypertension following repair of congenital diaphragmatic hernia [51]. Anesthetic doses of fentanyl analgesia (25 mcg/kg) have been shown to blunt the stress hypertensive pulmonary response to broncho-carinal stimulation in infants following congenital cardiac surgery [ 171. Monitoring: description of crises

Fig. 3. Photomicrograph of a terminal pulmonary bronchiolar artery in case 17 showing an abnormally thick media (m). Magnification x 630

Monitoring and continuous recording of relevant variables allows the sequence of events to be analyzed. If only systemic arterial pressure is monitored, all that may be observed is a decline from normal to catastrophically low in less than 3 min (Fig. 1). Thus a “crisis” is a true emergency as death is imminent. If seen in isolation, such an observation might provoke therapies such as intravenous epinephrine or norepinephrine which could well aggravate the pulmonary hypertension. A rise in right atria1 pressure (another commonly monitored variable) precedes the fall in systemic pressure, giving some clue to the etiology, but this rise is often not substantial and thus non-specific. A rise in pulmonary arterial or right ventricular systolic end diastolic pressures precedes systemic hypotension and is a signal for intervention. P,,O, falls abruptly, confirming the physiological effect of the rise in pulmonary vascular resistance. This fall occasionally precedes the rise in pulmonary artery pressure. Transcutaneous oximetry is an extremely useful monitoring method, but alone is a relatively non-specific parameter; the P,,O, may fall as a consequence of widening of the AVO, difference, a decrease in peripheral perfusion (systemic

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vasoconstriction), an increase in pulmonary vascular resistance causing decreased effective pulmonary blood flow, or mechanical ventilatory problems resulting in hypoxia and hypoxemia [5]. Nevertheless, any of these reasons for a fall in P,,O, are also potential stimulants for, or related to, the development of pulmonary hypertensive crises and mandate treatment. All of the variables monitored together give a recognizable and characteristic response pattern that makes recognition of a pulmonary vascular crisis easy and reproducible. Pathphysiology

of crises

The hallmark of the pulmonary hypertensive crisis is its paroxysmal nature. The implication is that these children have a very reactive pulmonary vascular bed. This physiology seems to occur in the setting of persistent fetal muscularization or with the increase in medial thickness and distal muscularization secondary to high pulmonary artery pressure and flow in congenital heart disease [23]. Patients with the more severe pulmonary vascular disease characterized by intimal changes and thinning of arteriolar muscle do not behave in this way and have a more fixed resistance problem. Unlike the preoperative situation and unlike the neonate with persistent fetal circulation (PFC), potential right to left shunt pathways such as septal communications or a ductus are often not present after surgical repair [5, 11, 24, 33, 531. Thus when a critical rise in pulmonary vascular resistance occurs against which the right ventricle cannot maintain its previous stroke volume, it “fails” with elevation in right ventricular diastolic pressure and there is an immediate fall in the preload of the left ventricle, resulting in systemic hypotension. It may be that in high risk patients, the foramen ovale should be left patent. Thus postoperatively, although hypoxemia would develop due to a right to left shunt, volume would be available for the left ventricle to maintain system output. Conversely, from a therapeutic standpoint, when tolazoline (or other vasodilator) is infused into the right atrium in postoperative patients, it must go through the pulmonary circuit if there is forward flow, whereas in PFC it may be shunted right to left and act predominately as a systemic vasodilator which in part may explain the different response to vasodilator therapy that is seen in the postoperative patient. The final therapeutic option would be to institute extracorporeal membrane oxygenator support. From the morphological point of view, we have established that the pulmonary vascular substrate of the pulmonary hypertensive crisis is completely different to that in children dying postoperatively of irreversible pulmonary vascular disease. However, little is known about the cause of the pulmonary vascular reactivity which is its hallmark. Physiologically, the pulmonary circulation is very sensitive to catecholamines, both exogenous and endogenous. Moreover, since pulmonary arterial sympathetic adrenergic sensitivity is alpha predominant, catecholamines with mixed alpha and beta activity tend to have predominately constrictor effects in the pulmonary

circulation [20, 26, 29, 321. Hypoxic stimulation of the precapillary arteriolar resistance region is perhaps the single most potent vasoconstrictor. This can be caused by inadequate alveolar oxygen concentrations (alveolar hypoxia), reduced mixed venous oxygen saturations (precapillary arteriolar hypoxemia), or arterial desaturation (capillary hypoxemia) [2, 3, 9, 341. The consequences of reduced pulmonary blood flow and systemic cardiac output are the very factors which stimulate pulmonary arteriolar vasoconstriction most strongly, i.e., hypoxia, acidosis, catecholamine release [3, 19,21,22,40,46]. The pulmonary circulation cannot be separated from the systemic circulation and treated in isolation as left ventricular failure potentiates mechanisms which provoke vasoconstriction [ll, 441. Left ventricular function must be optimized but ideally with methods (e.g. afterload reduction, isoproterenol, low dose dopamine) that do not have pulmonary vasoconstrictive side effects (i.e. avoid alpha adrenergic agonists). Our definition of crisis is somewhat different to that of other reports in the literature [24,53]. We reserve the term “crisis” for patients who have acute pulmonary hypertension accompanied by systemic hypotension and presumably low cardiac output, and refer to other episodes as pulmonary hypertensive events. Wheller et al. defined postoperative pulmonary hypertensive crisis as an acute pulmonary hypertensive event with resultant hypoxemia [53]. In two of their three cases, tolazoline infusions reduced the PA pressures and improved the PaO, . However, except in their first case, marked systemic hypotension did not appear to be a component. The report from the Brompton Hospital of 15 patients used a definition based on P,/Pa ratio greater than 0.8 but did not specifically comment on absolute systemic pressure values [24]. Pulmonary vasodilator

Our observations confirm that oxygen hyperventilation is the best pulmonary vasodilator in the acute setting [12]. The ideal pharmacological agent has not been found. Many agents have been reported as having pulmonary vasodilating properties: calcium channel blockers, aminophylline, alpha blockers, beta agonists, nitrates, and prostaglandins [l, 4, 6-8, 10, 12, 13, 25, 27, 28, 30, 31, 35-39,43,45,48-501. However, no single agent was consistently effective in our or other series, nor can we assume that agents effective in diseases such as primary pulmonary hypertension are necessarily effective in the setting of postoperative pulmonary hypertension of infancy. Tolazoline, an alpha blocker and histamine agonist, was the agent most commonly effective in our series [5, 12, 13, 24, 33, 41, 47, 531. One of the reported difficulties with tolazoline is rapid systemic vasodilation and hypotension [52]. We found that this was easily managed by following any bolus of tolazoline with a bolus of calcium chloride and had no difficulty in this area. We had none of the other reported complications with tolazoline such as gastric bleeding, though prophylaxis with antacids was routinely used. It is not clear what governs variation in responsiveness to the various agents identi-

633

fied as a pulmonary vasodilator. Patients not responding to one agent may respond to another so that introducing a new agent to non-responders is worthwhile. Although 6 patients died, all but 1 evidenced pulmonary vasodilation in response to one or more therapies at some stage. Frustratingly, they became less responsive over time, one agent after another becoming ineffective.

Conclusions Pulmonary hypertensive crises are relatively common in high risk infants following surgery for congenital heart disease. Crises have an inherently “self-reinforcing” character to their development which mandates rapid and aggressive therapies. These episodes are potentially lethal but can be responsive to available treatment techniques. Prevention and early suppression of events are very important since once initiated, these episodes cluster; high dose analgesia and paralysis are extremely useful. Specific monitoring is helpful and definitely indicated in high risk patients. The ideal pulmonary vasodilating regimen has not yet been developed, but hyperoxygenation with manual hyperventilation and tolazoline are, at present, the most frequently efficacious and most fully described vasodilators available. References 1. Artman

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Pulmonary hypertensive crises following surgery for congenital heart defects in young children.

In this clinical study, 20 high risk infants and neonates were monitored to identify and characterize pulmonary hypertensive crises following surgery ...
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