Impact of phrenic nerve palsy on late Fontan circulation

Journal Pre-proof Impact of phrenic nerve palsy on late Fontan circulation Motoki Komori, MD, Takaya Hoashi, MD, PhD, Masatoshi Shimada, MD, PhD, Masataka Kitano, MD, Hideo Ohuchi, MD, PhD, Kenichi Kurosaki, MD, Hajime Ichikawa, MD, PhD PII:

S0003-4975(19)31690-X

DOI:

https://doi.org/10.1016/j.athoracsur.2019.09.064

Reference:

ATS 33208

To appear in:

The Annals of Thoracic Surgery

Received Date: 22 January 2019 Revised Date:

18 September 2019

Accepted Date: 19 September 2019

Please cite this article as: Komori M, Hoashi T, Shimada M, Kitano M, Ohuchi H, Kurosaki K, Ichikawa H, Impact of phrenic nerve palsy on late Fontan circulation, The Annals of Thoracic Surgery (2019), doi: https://doi.org/10.1016/j.athoracsur.2019.09.064. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 by The Society of Thoracic Surgeons

Phrenic nerve palsy in Fontan patients. Komori et al. 1

Impact of phrenic nerve palsy on late Fontan circulation

Running head: Phrenic nerve palsy in Fontan patients

Motoki Komori, MD1, Takaya Hoashi, MD, PhD1, Masatoshi Shimada, MD, PhD1, Masataka Kitano, MD2, Hideo Ohuchi, MD, PhD2, Kenichi Kurosaki, MD2, Hajime Ichikawa, MD, PhD1

Departments of Pediatric 1Cardiovascular Surgery and 2Cardiology, National Cerebral and Cardiovascular Research Center, Suita, Osaka, Japan 564-8565

Classifications: CHD; phrenic nerve palsy; single ventricle; Fontan

Meeting presentation: Poster presentation at STS 55th Annual Meeting – 27 January 2019, San Diego, California

Word count: 3630 words

Address correspondence to: Takaya Hoashi, MD, PhD

Address: 6-1, Kishibe-shinmachi, Suita, Osaka, Japan 564-8565

E-mail Address: [email protected]

Phrenic nerve palsy in Fontan patients. Komori et al. 2

Abstract

Background: Although adverse effects of phrenic nerve palsy (PNP) on early Fontan circulation have been reported, detailed late impact remains unclear.

Methods: Of 218 patients undergoing extracardiac total cavo-pulmonary connection (EC-TCPC) between 1995 and 2008, 160 who all underwent cardiac catheter examination, spirometry, and exercise capacity testing 10 years after the operation were enrolled. The cohort was divided into two groups: with (n=21) or without PNP (control group, n=139). The patients with PNP were further divided into the recovered PNP group (n=10) and the persistent PNP group (n=11). All but two patients who developed PNP (90.9%) underwent diaphragmatic plication. There was no difference in hemodynamic indices at pre-Fontan evaluation among the three groups.

Results: Ten years after the Fontan procedure, the averaged forced vital capacity was 81 ± 18 % of predicted in the control group, 86 ± 17 % in the recovered PNP group, and 56 ± 12 % in the persistent PNP group (p < 0.0001). Peak oxygen consumption was linearly correlated to the forced vital capacity (r = 0.222, p = 0.009). There was no significant difference in the peak oxygen consumption between groups. Significant veno-venous collaterals into the diaphragm

Phrenic nerve palsy in Fontan patients. Komori et al. 3

from lower body to pulmonary vein(s) or atria more frequently developed in patients who underwent diaphragmatic plication compared to those who did not (p<0.0001).

Conclusions: Persistent PNP resulted in reduced forced vital capacity; however, its influence on exercise intolerance could not be identified. Diaphragmatic plication should be reserved for patients who experience clinically-significant respiratory or haemodynamic sequelae of PNP.

Phrenic nerve palsy in Fontan patients. Komori et al. 4

Phrenic nerve palsy (PNP) occurs frequently in single ventricle patients undergoing cardiovascular surgery [1-3] and results in a restrictive ventilatory impairment. Since normal respiratory chest movement and negative intrathoracic pressure are essential for efficient passive pulmonary blood flow in the Fontan circulation [4, 5], restrictive ventilatory impairment has a negative impact on Fontan physiology [6]. Hence, PNP is a significant risk factor for high Fontan pathway pressure, prolonged pleural effusion, longer hospitalization, and frequent accumulation of ascites [1, 7].

On the other hand, the detailed impact of PNP on late Fontan circulation has not been fully investigated. Although both suppressed inspiration-derived hepatic venous flow and portal venous flow without normal expiratory augmentation were reported to continue even though the paralyzed diaphragm was plicated (fixed) [8], it was hypothesized that the influence of persistent PNP on late Fontan patients

Phrenic nerve palsy in Fontan patients. Komori et al. 5

might be minimal, because the type of breathing is theoretically changed from abdominal (diaphragmatic) breathing only to abdominal combined with chest (rib cage) breathing by 10 years postoperatively.

The objective of this study therefore was to assess the impact of PNP on respiratory function, hemodynamics, and exercise capacity 10 years after Fontan procedure.

Phrenic nerve palsy in Fontan patients. Komori et al. 6

Patients and Methods

Patients

The National Cerebral and Cardiovascular Center Institutional Review Board approved this retrospective study (M23-002-4), and opt-out consent was obtained instead of individual written informed consent. Of 218 patients undergoing extracardiac total cavo-pulmonary connection (EC-TCPC) following bidirectional Glenn without antegrade pulmonary blood flow between 1995 and 2008, 160 patients (73.4%) who all underwent cardiac catheter examination, spirometry, and exercise capacity testing 10 years after the EC-TCPC were enrolled in this study (Fig. 1).

21 patients out of 218 (13.1%) developed PNP. PNP occurred before second stage bidirectional Glenn (at palliative surgery) in five patients (23%), at bidirectional Glenn in 11 (50%), and at Fontan operation in six (27%). Nineteen of 21 patients (90.5%) underwent diaphragmatic plication (fixation) using the “accordion technique” as described by Schwartz et al. [8]. Repeated plications were required in one patient (5%); no patient underwent plications on both sides. Ten years following EC-TCPC, the paralyzed diaphragm regained synchronized

Phrenic nerve palsy in Fontan patients. Komori et al. 7

respiratory movement to the contralateral diaphragm in 10 patients (recovered PNP group) and remained unchanged in 11 patients (persistent PNP group) (Fig. 1).

Patient characteristics are summarized in Table 1. Distribution of main diagnoses, age, weight, and frequency of fenestration creation at Fontan procedure were not significantly different among the three groups. Hemodynamic indices at pre-Fontan evaluation such as mean pulmonary artery pressure, pulmonary vascular resistance, pulmonary artery index, systemic ventricular end-diastolic volume, systemic ventricular ejection fraction, and systemic ventricular end-diastolic pressure were also not significantly different among the three groups (Table 2).

Study method

This is a retrospective, non-randomized, single institutional study; variables evaluated 10 years following EC-TCPC were as follows: 1) Spirometry (forced vital capacities [FVC] and forced expiratory volumes in one second [FEV1.0]), 2) Exercise capacity testing (peak oxygen consumption [pVO2] and anaerobic threshold [AT]), 3) Cardiac catheter examination (mean pulmonary artery pressure, pulmonary vascular resistance, cardiac index, systemic ventricular

Phrenic nerve palsy in Fontan patients. Komori et al. 8

end-diastolic pressure, systemic ventricular ejection fraction, and systemic ventricular end-diastolic pressure) and arterial oxygen saturation, and 4) Development of veno-venous collaterals on the diaphragm from systemic veins below the extra-cardiac conduit to pulmonary vein(s) or the atrium.

Both diagnosis and improvement of PNP were confirmed by diaphragm fluoroscopy. When PNP was suspected by chest X-ray findings, paradoxical respiratory motion, or effort ventilation during perioperative period, all patients underwent diaphragm fluoroscopy. During the study period, no one was newly discovered to have PNP at scheduled follow-up cineangiography after discharge.

Spirometry was repeated at least three times to ensure reproducibility. The test session was considered finished when the difference between the two largest FVC and FEV1.0 measurements was within 0.2L [10]. FVC and FEV1.0 were compared with predicted values as recommended by the Japanese Society of Pediatric Pulmonology [https://doi.org/10.5701/jjpp.19.164] and expressed as a percentage of

Phrenic nerve palsy in Fontan patients. Komori et al. 9

predicted. Exercise capacity testing was performed on a treadmill or a cycle ergometer with a ramp protocol according to the guidelines of the American Heart Association [11]. Cardiac catheter examinations were routinely performed once every five years following Fontan procedure, usually under sedation and with spontaneous unassisted ventilation.

All data were presented as means with standard deviations for continuous variables or numbers (%) for categorical variables. The groups’ comparison was performed using one-way ANOVA. Pearson correlation was used to estimate correlations among different variables. Statistical analyses were performed using SPSS statistics package, version 19 (SPSS Inc., IBM, Chicago, IL). P values of <0.05 were considered statistically significant.

Phrenic nerve palsy in Fontan patients. Komori et al. 10

Results

Spirometry

FVC in the control group, the recovered PNP group, and the persistent PNP group was 81 ± 18% of predicted, 86 ± 17% of predicted, and 56 ± 12% of predicted, respectively (p=0.00002) (Fig. 2A). Reduced FVC was observed for all three groups; FVC for the persistent PNP group was however significantly lower than that of the control group (p=0.00001) and recovered PNP group (p=0.003). FEV1.0 for the control group, the recovered PNP group, and the persistent PNP group was 91.4 ± 14.2% of predicted, 101.7 ± 17.3% of predicted, and 91.2 ± 20.9% of predicted, respectively (p=0.11) (Fig. 2B).

Cardiac catheter examination

Mean pulmonary arterial pressure for the control group, the recovered PNP group, and the persistent PNP static group was 9.3 ± 2.1 mmHg, 9.4 ± 1.6 mmHg, and 11.5 ± 2.8 mmHg, respectively (p=0.005) (Table 3). Mean pulmonary arterial pressure for the persistent PNP group was significantly higher than that of the control group (p=0.004). Arterial oxygen saturation for

Phrenic nerve palsy in Fontan patients. Komori et al. 11

the control group, the recovered PNP group, and the persistent PNP group was 94.6 ± 2.8%, 95.2 ± 2.4%, and 92.1 ± 4.6%, respectively (p=0.035) (Table 3). Other hemodynamic indices, such as pulmonary vascular resistance, cardiac index, systemic ventricular ejection fraction, and end-diastolic pressure did not differ among the three groups (Table 3).

Exercise capacity testing

pVO2 for the control group, the recovered PNP group, and the persistent PNP group was 29.6 ± 6.5 ml/minute/kg, 33.5 ± 5.0 ml/minute/kg, and 26.3 ± 3.8ml/minute/kg, respectively (p=0.05) (Fig. 3A). pVO2 for the persistent PNP group was not significantly lower than that of the control group (p=0.29). AT for the control group, the recovered PNP group, and the persistent PNP group was 17.9 ± 4.6 ml/minute/kg, 20.5 ± 2.6 ml/minute/kg, and 17.3 ± 3.8 ml/minute/kg, respectively (p=0.22) (Fig. 3B).

Linear regression analysis showed FVC in all study cohorts was positively correlated with pVO2 (r=0.222, p=0.009) (Fig. 4A), whereas FEV1.0 was not correlated (r=0.0145, p=0.869) (Fig. 4B). Two patients with a past history of surgery via thoracotomy and also without

Phrenic nerve palsy in Fontan patients. Komori et al. 12

impairments of respiration and hemodynamics during the early postoperative period did not undergo diaphragm plication. Their PNP was persistent, and FVC and pVO2 were below predicted normal (51.5 % and 30.1 ml/min/kg in one, 64.2 % and 27.0 ml/min/kg in the other).

Development of veno-venous collaterals

Significant veno-venous collaterals on the diaphragm from systemic veins below the extra-cardiac conduit to pulmonary vein(s) or the atrium developed in seven patients (Fig. 5). The prevalence of the development of significant veno-venous collaterals on the diaphragm was 1.4% (2/139) in the control group, 10% (1/10) in the recovered PNP group, and 36% (4/11) in the persistent PNP group (p=0.0001). Whereas five of 19 patients (26.3%) who underwent diaphragmatic plication developed significant veno-venous collaterals on the diaphragm, only two of 141 patients (1.4%) who did not undergo diaphragmatic plication did (p=0.0003). Both patients in the persistent PNP group who did not undergo plication were free of veno-venous collaterals at follow up angiography.

Phrenic nerve palsy in Fontan patients. Komori et al. 13

Comment

The study demonstrated that FVC 10 years after Fontan operation is subnormal regardless of the past PNP. The restrictive ventilatory impairment was the worst in the persistent PNP group even with diaphragm plication. Critical impairment of Fontan hemodynamics or exercise capacity, contrary to our speculation, was not associated with persistent PNP within 10 years after Fontan procedure. Although, the higher Fontan pathway pressure and the lower oxygen saturation in the persistent PNP group were seen as compared to the control group, the numbers are acceptable (central venous pressure = 11.5 ± 2.8 mmHg, oxygen saturation = 92.1 ± 4.6 %). This may be because the slope of the significant correlation between FVC and pVO2 is small. In our study, subnormal FVC did not lead directly to significant differences in pVO2 or AT between the control group and the persistent PNP group.

Restrictive ventilatory impairment was reported to be seen in about half of grown up Fontan patients as well as other grown up congenital heart disease patients [12]. Restrictive ventilatory impairment was thought to be caused by prenatal and early postnatal underdevelopment of alveolar, congenital, or acquired airway obstruction; weakness of respiratory musculature; or

Phrenic nerve palsy in Fontan patients. Komori et al. 14

skeletal chest deformity which was sometimes a result of prior operations [13]. Surgical interventions are the other factor which might cause the limited lung volume by direct injury [11], pleural adhesions, and pulmonary vascular histological changes by nonspecific inflammation [13]. There are some patients in the control group, who showed markedly reduced FVC (Figure 4) Interestingly, FEV1.0 was well maintained in the majority of our study cohorts with or without PNP. After the diaphragm is plicated, diaphragmatic movement is no longer paradoxical, but a plicated diaphragm is immobile and sometimes remains elevated slightly if PNP did not resolved. This may explain the discrepancy between the normalized FEV1.0 and reduced FVC.

Fontan pathway pressure is believed to increase when there is only a little negative pressure effect of the lungs [4, 5]. This might explain why slightly higher mean pulmonary arterial pressure was observed in the persistent PNP group [8]. Fortunately, this impairment in FVC by PNP did not significantly affect the other hemodynamic variables such as pulmonary vascular resistance, cardiac index, ventricular ejection fraction, or ventricular end-diastolic pressure. Therefore, pVO2 and AT in the persistent PNP group were not statistically inferior to those in the control group. From our observation, persistent PNP reduced FVC, but its effect on

Phrenic nerve palsy in Fontan patients. Komori et al. 15

hemodynamics or exercise capacity in the Fontan circulation was minimal until at least 10 years following Fontan procedure.

Systemic arterial desaturation in the persistent PNP group may be due to the hypoventilation in the unilateral lung. Desaturation may also be caused by the presence of veno-venous collaterals from the Fontan pathway to the pulmonary veins or atrium, which was reported to develop when Fontan pathway pressure is high [14]. As the diaphragmatic plication itself causes surgical injury to the diaphragm, this might lead to a development of massive collaterals on the plicated diaphragm even after PNP was resolved. Fortunately, in the present study, we did not encounter clinically detrimental desaturation (PNP group vs Control group; 94.6 ± 2.2 vs. 92.1 ± 4.6).

Diaphragmatic plication is indicated for respiratory symptomatic patients with a paralyzed hemi-diaphragm. Its favorable acute effect on respiratory function in pediatric population was reported [2, 15, 16]. In our series, diaphragmatic movement regained in about a half of the patients who developed PNP with or without subsequent diaphragmatic plication. Recovery of diaphragmatic function was reported to occur from six to twelve months postoperatively [2, 3, 17, 18]. This would explain why no late adverse outcomes were observed in the recovered PNP

Phrenic nerve palsy in Fontan patients. Komori et al. 16

group. From a surgical view point, further phrenic nerve injury should be avoided at the time of plication. A linear plication by the accordion technique should be selected rather than circumferential plication. In addition, diaphragmatic plication should be avoided [19], if the respiratory symptom is tolerable, because the diaphragmatic plication procedure itself can be a cause of veno-venous collaterals around the diaphragm.

Study limitations

The study described herein is a retrospective single-center study involving a limited number of patients who developed PNP. Due to the small numbers of patients, statistical power was limited. Impact from airway obstruction, developmental disorders, and skeletal chest deformity derived from scoliosis, funnel chest, or past history of surgery via thoracotomy on respiratory function could not be taken into account.

In summary, Persistent PNP reduced forced vital capacity; however, it did not result in clinically significant impairment of Fontan hemodynamics and exercise capacity until at least 10

Phrenic nerve palsy in Fontan patients. Komori et al. 17

years following Fontan operation. Diaphragmatic plication should be avoided as much as possible to prevent later development of veno-venous collaterals on the diaphragm.

Phrenic nerve palsy in Fontan patients. Komori et al. 18

References

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Ovroutski S, Alexi-Meskishvili V, Stiller B, et al. Paralysis of the phrenic nerve as a risk factor for suboptimal Fontan hemodynamics: Eur J Cardiothoracic Surg. 2005;27;561-565.

2.

Baker CJ, Boulom V, Reemtsen BL, Rollins RC, Starnes VA, Wells WJ. Hemidiaphragm plication after repair of congenital heart defects in children: quantitative return of diaphragm function over time. J Thorac Cardiovasc Surg. 2008;135:56-61.

3.

Smith BM, Ezeokoli NJ, Kipps AK, Azakie A, Meadows JJ. Course, predictors of diaphragm recovery after phrenic nerve injury during pediatric cardiac surgery. Ann Thorac Surg. 2013;96:938-42.

4.

Penny DJ, Redington AN. Doppler echocardiographic evaluation of pulmonary blood flow after the Fontan operation; Br Heart J 1991;66:372-4.

5.

Redington AN, Penny D, Shinebourne EA. Pulmonary blood flow after total cavopulmonary shunt; Br Heart J 1991;65:213-7.

Phrenic nerve palsy in Fontan patients. Komori et al. 19

6.

Callegari A, Neidenbach R, Milanesi O, et al. A restrictive ventilatory pattern is common in patients with univentricular heart after Fontan palliation and associated with a reduced exercise capacity and quality of life. Congenit Heart Dis. 2019;14:147-155.

7.

Amin Z, McElhinney DB, Strawn JK, et al. Hemidiaphragmatic paralysis increases postoperative morbidity after a modified Fontan operation: J Thorac Cardiovasc Surg 2001;122:856-62.

8.

Hsia TY, Khambadkone S, Bradley SM, de Leval MR. Subdiaphragmatic venous hemodynamics in patients with biventricular and Fontan circulation after diaphragm plication. J Thorac Cardiovasc Surg. 2007;134:1397-405.

9.

Schwartz MZ, Filler RM. Plication of the diaphragm for symptomatic phrenic nerve paralysis. J Pediatr Surg. 1978;13:259-63.

10. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 2005;26:319-38.

11. Paridon SM, Alpert BS, Boas SR, et al; American Heart Association Council on Cardiovascular

Disease

in the Young,

Committee

on Atherosclerosis,

Phrenic nerve palsy in Fontan patients. Komori et al. 20

Hypertension, and Obesity in Youth. Clinical stress testing in the pediatric age group: a statement from the American Heart Association Council on Cardiovascular

Disease

in the Young,

Committee

on Atherosclerosis,

Hypertension, and Obesity in Youth. Circulation. 2006 18;113:1905-20.

12. Ginde S, Bartz PJ, Hill GD, et al. Restrictive lung disease is an independent predictor of exercise intolerance in the adult with congenital heart disease. Congenit Heart Dis. 2013;8:246-54.

13. Opotowsky AR, Landzberg MJ, Earing MG, et al. Abnormal spirometry after the Fontan procedure is common and associated with impaired aerobic capacity. Am J Physiol Heart Circ Physiol. 2014;307:H110-7.

14. Poterucha JT, Johnson JN, Taggart NW, et al. Embolization of Veno-venous Collaterals after the Fontan Operation Is Associated with Decreased Survival. Congenit Heart Dis. 2015;10:E230-6.

15. Tönz M, von Segesser LK, Mihaljevic T, Arbenz U, Stauffer UG, Turina MI. Clinical implications of phrenic nerve injury after pediatric cardiac surgery. J Pediatr Surg. 1996;31:1265-7.

Phrenic nerve palsy in Fontan patients. Komori et al. 21

16. Floh AA, Zafurallah I, MacDonald C, Honjo O, Fan CS, Laussen PC. The advantage of early plication in children diagnosed with diaphragm paresis. J Thorac Cardiovasc Surg. 2017;154:1715-1721.

17. Kunovsky P, Gibson GA, Pollock JC, Stejskal L, Houston A, Jamieson MP. Management of postoperative paralysis of diaphragm in infants and children. Eur J Cardiothorac Surg. 1993;7:342-6.

18. de Leeuw M, Williams JM, Freedom RM, Williams WG, Shemie SD, McCrindle BW.. Impact of diaphragmatic paralysis after cardiothoracic surgery in children; J Thorac Cardiovasc Surg 1999;118:510-7.

19. Georgiev S, Konstantinov G, Latcheva A, Mitev P, Mitev I, Lazarov S. Phrenic nerve injury after paediatric heart surgery: is aggressive plication of the diaphragm beneficial? Eur J Cardiothorac Surg. 2013;44:808-12.

Phrenic nerve palsy in Fontan patients. Komori et al. 22

Table 1: Patient characteristics. Control PNP

Recovered

Persistent PNP

Number of patients

139

10

27 (19)

1(10)

6 (4)

2 (20)

Heterotaxy

23 (17)

2 (20)

Others

83 (60)

5 (50)

Age at Fontan (years)

2.4 ± 1.8

1.5 ± 0.6

Weight at Fontan (kg)

10.4 ± 3.6

10.0 ± 2.7

14 (10)

2 (20)

SP shunt

67 (48)

8 (80)

Branch PA plasty

38 (27)

1 (10)

TAPVC repair

6 (4)

0 (0)

AVVP/R

6 (4)

0 (0)

-

10 (100)

Diagnosis [n (%)] TA HLHS and its variant

Fenestration at Fontan [n (%)] Previous operation [n (%)]

Diaphragmatic plication [n (%)]

PNP: phrenic nerve palsy, ANOVA: analysis of variance, TA: tricuspid atresia, HLHS: hypoplastic left heart syndrome, SP shunt: systemic pulmonary artery shunt, PA: pulmonary artery, TAPVC: total anomalous pulmonary vein, AVVP/R: atrioventricular valve plasty/replacement. *: p< 0.05 vs. recovered PNP group, †: p<0.05 vs. control group.

Phrenic nerve palsy in Fontan patients. Komori et al. 23

Table 2: Pre-Fontan cardiac catheter examination.

Control Recovered PNP

Persistent PNP

Number of patients Age at examination (years, mean ± SD)

139

10

1.8 ± 1.7

1.0 ± 0.4

11.7 ± 3.3

14.3 ± 3.4

1.5 ± 0.8

1.7 ± 0.7

280 ± 117

307 ± 162

162 ± 54

171 ± 42

59.8 ± 9.8

55.5 ± 9.9

7.3 ± 3.1

9.5 ± 2.9

1.9 ± 1.3 mPAP (mmHg, mean ± SD) 11.8 ± 2.9 PVR (WU/ m2, mean ± SD) 1.8 ± 0.9 PAI (mean ± SD) 255 ± 102 SVEDV (% of predicted normal value, mean ± SD) 149 ± 49 SVEF (%, mean ± SD) 61.8 ± 10.4 SVEDP (mmHg, mean ± SD) 6.9 ± 2.4 SD: Standard deviation, mPAP: mean pulmonary arterial pressure, PVR: pulmonary vascular resistance, PAI: pulmonary artery index, SVEDV: systemic ventricular end-diastolic pressure, SVEF: systemic ventricular ejection fraction, SVEDP: systemic ventricular end-diastolic pressure. *: p< 0.05 vs. recovered PNP group, †: p<0.05 vs. control group.

Phrenic nerve palsy in Fontan patients. Komori et al. 24

Table 3: Cardiac catheter examination 10 years following Fontan procedure.

Control Recovered PNP

Persistent PNP

Number of patients

139

Age at examination (years, mean ± SD)

10

13.6 ± 2.9

11.8 ± 2.3

40.2 ± 14.6

32.5 ±

0.98 ± 0.1

0.98 ± 0.1

9.3 ± 2.1

9.4 ± 1.6

2.0 ± 7.2

1.3 ± 0.5

3.0 ± 0.6

3.1 ± 0.5

55.6 ± 8.6

51.3 ± 9.5

7.5 ± 2.9

5.6 ± 2.5

94.6 ± 2.8

95.2 ±

14.1 ± 4.8 Weight (kg, mean ± SD) 8.1

30.2 ± 9.0

Qp/Qs (mean ± SD) 0.97 ± 0.1 mPAP (mmHg, mean ± SD) 11.5 ± 2.8† PVR (WU/ m2, mean ± SD) 1.4 ± 0.5 CI (L/minute/m2, mean ± SD) 2.9 ± 0.5 SVEF (%, mean ± SD) 58.8 ± 8.5 SVEDP (mmHg, mean ± SD) 8.2 ± 3.4 Arterial oxygen saturation (%, mean ± SD) 2.4

92.1 ± 4.6†

SD: Standard deviation, Qp/Qs: systemic to pulmonary blood flow ratio, mPAP: mean pulmonary arterial pressure, PVR: pulmonary vascular resistance, CI: cardiac index, SVEF: systemic ventricular ejection fraction, SVEDP: systemic ventricular end-diastolic pressure. *: p< 0.05 vs. recovered PNP group, †: p<0.05 vs. control group.

Phrenic nerve palsy in Fontan patients. Komori et al. 25

Figure legends

Figure 1:

Patient selection. EC-TCPC: total cavo-pulmonary connection with extra-cardiac conduit. PNP: phrenic nerve palsy.

Figure 2:

(A) Forced vital capacity (FVC) and (B) forced expiratory volume in one second (FEV1.0) 10 years following Fontan procedure. PNP: phrenic nerve palsy.

Figure 3: (A) Peak oxygen consumption (pVO2) and (B) anaerobic threshold (AT) 10 years following Fontan procedure. PNP: phrenic nerve palsy.

Figure 4:

Linear regression between (A) forced vital capacity (FVC) and peak oxygen consumption (pVO2) and (B) forced expiratory volume in one second (FEV1.0) and pVO2, 10 years following Fontan procedure. PNP: phrenic nerve palsy.

Figure 5: Veno-venous collaterals from right pulmonary artery to atria (white arrows) in a patient with remaining phrenic nerve palsy.

Phrenic nerve palsy in Fontan patients. Komori et al. 26

Abbreviations and Acronyms AT

= Anaerobic threshold

EC-TCPC

= Total cavopulmonary connection with extra-cardiac conduit

FEV1.0

= Forced expiratory volume per second

FVC

= Forced vital capacity

PNP

= Phrenic nerve palsy

pVO2

= Peak oxygen consumption

EC-TCPC: N = 218 (1995-2008) N = 58 10 years’ follow-up*1 completed: N = 160

*1: Cardiac catheter examination Spirometry Exercise capacity testing

*2: Diaphragmatic plication PNP: N = Yes : N = 19 No : N = 2 10 years after Fontan

21*2

Control: N = 139

recovered PNP : N = 10

persistent PNP : N = 11

FVC (% of predicted) 140 120

FEV1.0 (% of predicted)

p = 0.1

p = 0.00001

140

p = 0.94 p = 0.003

100

80

80

40

60

86 ± 17 81 ± 18

56 ± 12

102 ± 17 91 ± 14

91 ± 21

40 20

20

0

0

(A)

p = 0.26

120

100

60

p = 0.1

recovered persistent

Control

PNP

PNP

(B)

recovered persistent

Control

PNP

PNP

pVO2 (ml/min./kg)

p = 0.29 p = 0.16 p = 0.04

AT (ml/min./kg)

40

40

p = 0.9

30

30

p = 0.2 p = 0.3

33.5 ± 5.0 20

20

29.6 ± 6.5

26.3 ± 3.8 10

10

20.5 ± 2.6 17.9 ± 4.6

0

0 recovered persistent

(A)

17.3 ± 3.8

Control

PNP

PNP

recovered persistent

(B)

Control

PNP

PNP

〇: Control ▲: recovered PNP ■: persistent PNP(DP(-): ☒)

r = 0.222 p = 0.009

〇: Control r ▲: recovered PNP p ■: persistent PNP(DP(-): ☒)

= 0.0145 = 0.869

☒ ☒ ☒

(A)

FVC (% of predicted)

☒

(B)

FEV1.0 (% of predicted)