A prospective randomized trial of delayed versus immediate repair of congenital diaphragmatic hernia

A Prospective

Randomized Trial of Delayed Versus Immediate of Congenital Diaphragmatic Hernia

Repair

By Masaki Nio, Gerald l-base, Jan Kennaugh, Kim Bui, and James B. Atkinson Los Angeles, California and Denver, Colorado l From March 1990 to January 1993, a randomized prospective study was performed to determine the optimal timing of surgery for infants with high-risk congenital diaphragmatic hernia (CDH). Thirty-two CDH patients who presented with respiratory distress within 12 hours after birth were randomly divided into two groups: Group A had early repair (within 6 hours), and group B had delayed repair (at 96+ hours). Extracorporeal membrane oxygenation (ECMO) was initiated in both groups as necessary. Fourteen patients were assigned to group A, and 16 were assigned to group 6. Two patients initially assigned to group A had acute deterioration, and their operations had to be postponed. Data were collected, but these patients were eliminated from the study. The two groups were comparable based on gestational age, birth weight, Bohn’s criteria, and oxygenation and ventilatory index. Nine of 12 group A patients (75%) survived, and 73 of 18 group B patients (72%) survived (P > .05, not significant). The ECMO requirements for the two groups were not significantly different (8 of 12 (67%) v 16 of 18 (89%); P > -05). Surgical intervention for bleeding complications related to ECMO was required in three of eight (38%) with immediate repair and seven of 16 (44%) with delayed repair (P > .05). There was no difference in survival nor incidence of ECMO between the two groups. This is the first prospective study of timing of hernia repair that supports the conclusions of earlier reports of retrospective studies. Copyright o 1994 by W.B. Saunders Company INDEX WORDS:

Diaphragmatic

hernia, congenital.

A

LTHOUGH extracorporeal membrane oxygenation support is a strong adjunct in the management of neonates with congenital diaphragmatic hernia (CDH),’ the optimal timing of diaphragmatic repair has been a subject of debate. Cases of neonatal CDH that present with immediate respiratory distress after birth have long been regarded as a surgical emergency.2 In contrast to this practice, a number of recent studies have shown deterioration of pulmonary function after repair.3-5 The end of the “honeymoon” period has frequently correlated with the completion of surgical repair of the diaphragm. These observations led to the hypothesis that survival could be enhanced and the requirement for

From the Division of Pediatric Surgery, Children’s Hospital, Los Angeles, CA, and the Divisions of Neonatology and Pediatric Sutgety, Children’s Hospital, Denver, CO. Presented at the 26th Annual Meeting of the Pacific Association of Pediatric Surgeons, Cairns, Queensland, Australia, May 9-14, 1993. Address reprint requests to James B. Atkinson, MD, 4650 Sunset B&f, Los Angeles, CA 90027. Copyright o 1994 by W.B. Saunders Company 0022-3468/9412905-0010$03.00/O

618

ECMO decreased by delaying surgical repair of the diaphragm. This report addresses the question of surgical timing by randomizing neonates whose CDH is symptomatic within 12 hours of life into two groups: early repair (within 6 hours of arrival) and delayed repair (at 2 96 hours of age). If ECMO is required, repair may be delayed until the conclusion of the ECMO run. The two groups are compared with regard to survival and ECMO requirements. MATERIALS AND METHODS This study was performed between March 1990 and December 1992 at two collaborating institutions. The protocol was approved by both institutional review boards. The criteria of patient eligibility for enrollment in the study were as follows: (I) gestational age of more than 34 weeks, (2) birth weight ~2.0 kg. (3) respiratory failure at less than 12 hours of age (eg, requiring oxygen/ ventilator), (4) in the study center at less than 12 hours of age, (5) absence of congenital heart disease, (6) absence of abdominal wall defect, (7) absence of other serious or life-threatening anomalies, and (8) absence of intracranial hemorrhage of more than grade I. After obtaining consent, 32 CDH patients who met the above criteria were randomly divided into two groups: group A had immediate repair, and group B had delayed repair. Group A patients had repair as early as possible after preoperative stabilization via vigorous medical management. ECMO was initiated after repair, when the oxygen index was 40 or greater for more than 2 hours (01 = mean aitway pressure x FIO?/PAO_TX 100). The patients in group B were operated on after stabilization for at least 96 hours (if not placed on ECMO). Patients in the delayed group had the diaphragm electively repaired when evidence of pulmonary hypertension had been absent for 24 hours. Presence of pulmonary hypertension was determined by echocardiographic findings and a right radial-to-aortic POZ gradient of more than 20 mm Hg. This group was treated with ECMO before and after repair, using the same 01 criterion as for group A. CDH repair in patients placed on ECMO before surgery was delayed until the patients could be weaned or until maximal pulmonary function was obtained. Therefore, group B patients had hernia repair no earlier than 96 hours and as late as 290 hours after birth. The name, sex, birth history. age at admission, ventilatory parameters, pre/postoperative management, surgical intervention, complications, and outcome were documented for each patient. Survival, ECMO requirements, and complications were compared between the two groups. Survival was defined as successful hospital discharge. Statistical analysis was performed using the x’ analysis for categorical variables and the Student’s t test for continuous variables; P values of < .05 were considered significant. All eligible patients for whom consent could be obtained were included. RESULTS

Of 32 patients, 14 were assigned to group A, and 18 were assigned to group B. Two patients initially assigned to group A had acute deterioration and were JournalofPediatricSurgety,

Vol29,No 5 (Mayb1994: ~~616-621

CONGENITAL DIAPHRAGMATIC

619

HERNIA

Table 1. Population Characteristics

Table 3. Treatment

Group B:

Immediate

Delayed

immediate

Delayed

Repair

Repair

Repair

Repair

ECMO:non-ECMO Gestational

age (wk)

38.4 r 2.5

Sex (M:F)

39.6 2 2.1

7:5

Birth weight (g)

I

5.1 c 2.6

3.8 * 1.7

7.2 ? 1.9

5.6 + 1.5

Maximum

01

38.9 + 21.3 (h)

1210 2 860.3 6.3 + 2.7

index: VI = mean airway pressure

Procedure

significant

as mean 2 SD. Oxygenrate.

placed on ECMO unrepaired. These patients were eliminated from the study, reducing group A to 12 patients. Twenty-nine patients presented with respiratory distress immediately after birth. The other three patients had cyanosis, tachypnea, or respiratory distress at 1, 2, and 3 hours (respectively). Other demographic characteristics are shown in Table 1. The two groups are comparable based on gestational age, sex, and birth weight. The 01 and ventilatory index (VI) were similar in both groups. Although Apgars at 1 minute were also similar in both groups, Apgars at 5 minutes were significantly higher in group A (P < *OS). Distribution of Bohn’s quadrant scoring6 among each group is shown in Table 2. There were more group B patients in Bohn’s group C (Pace, > 40 + VI > l,OOO), but the difference was not significant. Bohn’s group C criteria predict 100% mortality. Table 3 shows the treatment and outcome. Eight of 12 patients (67%) in group A and 16 of 18 (89%) in group B required ECMO. Although there was a higher incidence of ECMO in group B, the difference was not significant (P > .05). More patients were repaired with prosthetic patches in group B than in group A, but the difference was not significant (2 of 12 (17%) v 7 of 17 (41%), P > .05). Table 2. Bohn’s Quadrant, Defined as the Ventilatory

Group A

(patients) at discharge

16:2

NS

172.8 % 65.2

P < .Ol

10:2

10:7

NS

9:3

13:5

NS

63.5 + 63.5

NS

(d) 49.6 2 30.4

NOTE. Data for age are expressed Abbreviation:

as mean z SD.

NS. not significant.

Nine patients in group A and 13 in group B survived (9 of 12 (75%) v 13 of 18 (72%); not significant). The group assignment and clinical course of the patients are shown in Fig 1. Causes of death were analyzed (Table 4). Three group A patients died-one of acute cardiorespiratory failure 1 hour after surgery. This infant had acute deterioration during surgery and could not be cannulated for ECMO before death. The other two died of respiratory failure and cardiorespiratory failure after ECMO management at ages 12 and 25 days, respectively. Five group B patients died during or after ECMO management. One died of cardiorespiratory failure and hemorrhage at 9 days of age (before repair). The respiratory failure was unremitting, and the patient’s condition was complicated by ECMOrelated bleeding from a chest-tube site. The other four patients died after surgery. Two of them died of cardiopulmonary failure at ages 16 and 21 days, respectively. The other two died of respiratory failure at 12 and 29 days of age (respectively). Significant bleeding complications related to ECMO were seen in three of eight (38%) group A patients and seven of 16 (44%) group B patients (P > .05). Each patient underwent appropriate surgical intervention including exploratory laparotomy, thoracotomy, and wound exploration (Table 5). Mild intracranial hemorrhage (ICH) was seen in one non-ECMO 32

neonates

with

CDH

1 Randomization

I $ A:Immadiate

Group B

Repair

14

+

B:Delayed Repair 18

Protocol

Predicted wo)

(primary:patch)

index Required

to Achieve a Pco2 of Less Than 40 mm Hg

Mortality”

Alive:Dead

Age of survivors

x FIO, x lOO/Pao,. Ventilatory

x ventilatory

a:4 10.1 t- 2.9

P < .Ol

44.9 + 19.9 Not 1172 + 987.7 5.6 ? 2.8 1 signficant

NOTE. Except for sex, data are expressed ation index: 01 = mean airway pressure

Not

3168 -c 385

Apgar, 1 min

(patients)

Age at repair(h)

10:8

3180 r 503

Apgar, 5 min Maximum VI Age at admission

and Outcome

Group A:

Observed

Observed

No. of

Mortality

No. of

Mortality

Patients

(“4

Patients

(04

I7 violation 2

A = Pace, > 40 + VI < 1,000 6 = Paco2 < 40 + VI

70

< 1,000 C = Pace, > 40 + VI

14

4

25

4

0

> 1,000 D = Pace, < 40 + VI

100

1

100

6

67

57

2

0

2

50

> 1,000

5

20

6

0

s7 ECMO 8

non-ECMO 4

1, ECMO 16

non-ECMO 2.

Fig 1. Assignment of treatment groups and subsequent course. “Alive” denotes successful hospital discharge.

clinical

620

NIO ET AL

Table 4. Summary of Causes of Death

Table 5. Bleeding Complications During ECMO

No.of Deaths CaW3

Immediate

Respiratory failure after ECMO Failure to wean from ECMO

1 (12) -

Cardiorespiratoryfailure

1 (25)

after ECMO

Acute myocardial dysfunction after surgery

l(1)

Delayed 2 (12.29) 1 (9) 2 (16, 21) -

ImmediateRepair

DelayedRepair

Cannulation site

2

5+

Hemoperitoneum

0

2

Hemothorax

1

2t

NOTE. Hemoperitoneum

was complicated by cannulation site bleed-

ing in one patient (*) and by hemothorax in another(t).

NOTE. Numbers in parentheses denote age at time of death (in days).

patient in each group, after enrollment in this study. No patient had intracranial hemorrhage related to ECMO. DISCUSSION

The opinion regarding optimal timing of repair for high-risk CDH has fluctuated over the last decade. Until 1985, emergency repair was the usual treatment of choice for CDH. Recently, the concept of emergency repair has been questioned because of the continued high mortality despite rapid repair. Several studies of the pathophysiology also support the skepticism regarding emergency repair. Vacanti et al’ reported that pulmonary vascular resistance was rapidly elevated by a variety of stimuli including endotracheal tube suctioning, loud noises, pain, and atelectasis. All these stimuli would be expected during repair of the diaphragm. Sakai et al8 reported that in most cases, compliance worsened in after emergency repair. This finding can be partially explained by the increased abdominal pressure associated with reduction of the viscera into a small abdominal cavity. Since 1985, the results of a number of studies have suggested that delay of diaphragmatic repair might have a beneficial effect on survival and might decrease the need for ECM0.9-11 A report by Breaux et a15 showed improved survival for a series of patients with delayed repair (compared with historical controls). In a similar study, Wilson et all2 found no improved survival with delayed repair. The current study was designed to provide an answer by prospective randomization of a group of CDH infants to early or late repair. Both groups were similar with regard to age at diagnosis, gestation, and maximal 01 and VI, reflecting no bias in the randomization. In addition, because only infants who became symptomatic within the first

12 hours of life were eligible for the study, we were dealing with the most severe cases. The survival rate was 73% for the entire study population. The survival rates for the two groups did not differ significantly (72% for the delayed group, 75% for the immediate group). ECMO was required more often in the delayed group (89% v 67%), but the difference was not significant. This trend to a lesser ECMO requirement in the early surgery group would have been eliminated by inclusion of the two infants who required ECMO before the protocol-directed early repair. Inclusion of these two infants would have increased the ECMO requirement in this group to 71%. There were three bleeding complications in the immediate group and nine in the delayed group. This finding could be partially explained by the higher need for ECMO in the latter group, but it is surprisingly low in the immediate group in view of the fact that many such infants required ECMO early in the preoperative course. The results of this study show neither an advantage for a rush to the operating room nor a clear advantage to a long delay for repair in a clinically stable infant. Clinical judgment and individualization of care are paramount. Infants who are clinically stable and can be operated on under conditions of satisfactory supportive care may undergo early repair. Those who are unstable early in their course or have evidence of persistent or intermittent pulmonary hypertension are best managed expectantly and can be placed on ECMO before repair, if necessary. While the overall survival rate of 73% is encouraging, the key to improving survival may well lie in the further development of lung transplantation,13 fetal intervention,14 and other innovative measures to correct pulmonary hypoplasia.

REFERENCES 1. Atkinson JB, Ford EG, Humphries B, et al: The impact of extracorporeal membrane support in the treatment of congenital diaphragmatic hernia. J Pediatr Surg 26:791-793, 1991 2. Gross RE: Congenital hernia of the diaphragm, in The Surgery of Infancy and Childhood. Philadelphia, PA, Saunders, 1953, pp 428-444 3. Geggel RL, Murphy JD, Langleben D, et al: Congenital

diaphragmatic hernia: Arterial structural changes and persistent pulmonary hypertension after surgical repair. J Pediatr 107:457464.1985 4. Cartlidge PHT, Mann NP, Kapila L: Preoperative stabilization in congenital diaphragmatic hernia. Arch Dis Child 61:12261228,1986 5. Breaux CW, Rouse TM, Cain WS, et al: Improvement in

CONGENITAL DIAPHRAGMATIC HERNIA

survival of patients with congenital diaphragmatic hernia utilizing a strategy of delayed repair after medical and/or extracorporeal membrane oxygenation stabilization. J Pediatr Surg 261333-338, 1991 6. Bohn D, Tamura M, Perrin D, et al: Ventilatory predictors of pulmonary hypoplasia in congenital diaphragmatic hernia, confirmed by morphologic assessment. J Pediatr 111:423-431,1987 7. Vacanti JP, Crone RK, Murphy JD, et al: The pulmonary hemodynamic response to perioperative anesthesia in the treatment of high-risk infants with congenital diaphragmatic hernia. J Pediatr Surg 19:672-679,1984 8. Sakai H, Tamura M, Hosokawa Y, et al: Effect of surgical repair on respiratory mechanics in congenital diaphragmatic hernia. J Pediatr 111:432-438,1987 9. Langer JC, Filler RM, Bohn DJ, et al: Timing of surgery for congenital diaphragmatic hernia: Is emergency operation necessary? J Pediatr Surg 23:731-734,1988

621

10. Hazebroek FWJ, Tibboel D, Bos AP, et al: Congenital diaphragmatic hernia: Impact of preoperative stabilization. A prospective pilot study in 13 patients. J Pediatr Surg 23:1139-1146, 1988 11. West KW, Bengston K, Rescorla FJ, et al: Delayed surgical repair and ECMO improves survival in congenital diaphragmatic hernia. Ann Surg 216:454-462,1992 12. Wilson JM, Lund DP, Lillehei CW, et al: Delayed repair and preoperative ECMO does not improve survival in high-risk congenital diaphragmatic hernia. J Pediatr Surg 27:368-375, 1992 13. Crombleholme TM, Adzick NS, Hardy K, et al: Pulmonary lobar transplantation in neonatal swine: A model for treatment of congenital diaphragmatic hernia. J Pediatr Surg 25:11-16, 1990 14. Harrison MR, Adzick NS, Longaker MT, et al: Successful repair in utero of a fetal diaphragmatic hernia after removal of herniated viscera from the left thorax. N Engl J Med 322:15221524,199O