Prospective Clinical Trials

Following are the prospective, randomized trials being conducted by the Center for Prospective Trials within the Department of Surgery at Children's Mercy Kansas City.

All of the studies being conducted investigate variables that do not allow the patient's course to vary from normal daily practice. Below are lists of completed prospective studies and studies that are currently in progress.

Completed prospective studies

Irrigation Versus No Irrigation at Operation for Children with Perforated Appendicitis

This is a prospective, randomized clinical trial involving patients who present to the hospital with perforated appendicitis. The aim of this study is to determine if irrigation of the abdominal area containing purulent material is beneficial at the time of laparoscopic appendectomy.

The power calculation was based on the postoperative abscess rate in our previous prospective study looking at antibiotic usage for perforated appendicitis (J Pediatr Surg 43:981-985, 2008). An unacceptable abscess rate needed to be chosen. Our current rate is 20%, or one-fifth of the patients presenting with perforation. If this were to increase by 15%, it would place just over one-third of the patients at risk which would be unacceptable. This is comparable to the 36% rejection level we used for our previous IRB approved trial (#07 02-031). Using a delta of 0.15 with an alpha of 0.05 and power of 0.8, the appropriate sample size becomes 109 patients in each arm. Therefore, we will anticipate enrolling 220 patients.

Subjects will be those children who are found to have severe inflammatory changes on imaging or a high clinical suspicion of perforation. Permission will be obtained from their parents or guardians prior to the operation. All of these children will be under stress prior to the operation and randomization. Therefore, we have requested waiving assent as we have done with our previous perforated appendicitis studies. 

The final decision to include a child in the study will made after appendiceal perforation has been visually confirmed during surgery. Perforation will be defined as an identifiable hole in the appendix or stool (fecalith) in the abdomen. The randomization assignment will be made known at the initiation of the operation and, at confirmation of perforation, the patient will utilize the next randomization slot.

The irrigation group will have a suction irrigator device set up with a one liter bag of normal saline. The surgeon must use at least 500 ml of this bag but may use as much as he chooses. The no irrigation group will have the suction irrigator set up without connection to saline. This will leave the surgeon with the capacity for suction only. After the operation, both groups will be managed according to the same protocol.

Ultrasound versus Landmark Guided Central Venous Access

The pediatric surgeons at Stanford University began this study with a definitive design in 100 patients and elicited Children's Mercy Kansas City's participation. The primary outcome variable is the number of percutaneous attempts needed to access the central vein for cannulation.

In the ultrasound (US) group, the US probe will be used intra-operatively to identify the location of the internal jugular vein. Once the vein is centered under the probe, an 18-gauge needle will be introduced with the help of the US probe.

In the landmark technique group, the procedure will be performed in a similar manner except that the surgeon will use known anatomic landmarks to decide where to obtain central venous access instead of using the US probe.

Single Incision versus Standard Laparoscopic Cholecystectomy

This is a definitive study in 60 patients who do not have cholecystitis. The primary outcome variable is operative time.

Likely, there are several variables that will show small differences between groups. This study will precisely quantify these variables to allow for adequate consultation from surgeons to families with children requiring removal of the gallbladder. The single-incision approach is not controlled for and the surgeons may vary in the technique and equipment they choose to employ. In general, we use the Covidien SILS™ port with an additional instrument placed along side.

Because the differences between the two groups are likely to be small and cosmesis is a proposed advantage of single-incision surgery, we are also using a validated tool to measure scar satisfaction at six weeks and six months after the operation.

Single Incision versus Standard Laparoscopic Appendectomy for Non-Perforated Appendicitis

St. Peter, Shawn D., MD; Adibe, Obinna O., MD; Juang, David, MD; Sharp, Susan W., PhD; Garey, Carissa L., MD; Laituri, Carrie A., MD; Murphy, J. Patrick, MD; Andrews, Walter S., MD; Sharp, Ronald J., MD; Snyder, Charles L., MD; Holcomb III, George W., MD, MBA; Ostlie Daniel J., MD. "Single Incision Versus Standard 3-Port Laparoscopic Appendectomy: A Prospective Randomized Trial." Annals of Surgery. 254, (2011): 586-590.

This is a definitive study in 360 patients with a 90% power. The primary outcome variable is post-operative infection.

Likely there are several secondary variables that will show small differences between groups. This study will precisely quantify these variables to allow for adequate consultation from surgeons to families with children with acute appendicitis. The single-incision approach is not controlled for and surgeons may vary in the technique and equipment they choose to employ.

Because the differences between the two groups are likely to be small and cosmesis is a proposed advantage of single-incision surgery, we are also using a validated tool to measure scar satisfaction at six weeks and six months after the operation.

Prospective Randomized Trial: Pain Management Strategy after Pectus Excavatum Repair

This is a single institution, prospective, randomized clinical trial comparing pain management strategies for patients who undergo the minimally invasive repair of a pectus excavatum deformity (Nuss operation).

One-hundred ten patients will be randomized in this definitive study. One group will undergo an attempt at epidural regional analgesia (epidural) for postoperative pain control. The other group will receive patient-controlled intravenous systemic analgesia (PCA) with continuous infusion and on-demand boluses.

Our retrospective data (J Pediatr Surg 43:79-82, 2008) suggest that each method holds potential advantages. Thus, this trial will define which method is more efficacious to apply to this population. The primary endpoint is length of postoperative hospitalization following the Nuss operation.

Prospective Evaluation of Blunt Renal Injury in Children

This will be a prospective, definitive data collection of all patients admitted to Children's Mercy Hospital and Phoenix Children's Hospital with blunt renal injury. There will be no study groups as this treatment algorithm is currently in use by surgeons at Children's Mercy Hospital. The medical records of these individuals will be reviewed and data points collected. Data collected include date of injury, age, gender, weight, side of renal injury, grade of injury, mechanism of injury, history of hypertension, last known blood pressure (if possible), radiologic studies, radiologic study results, associated injuries, initial and lowest daily hemoglobin and blood pressure levels for the first 5 days, daily urine output, daily urinalysis for up to 7 days, need for transfusion, type of transfusion, volume of transfusion, number of transfusion episodes, initial and any subsequent urinalysis results, any operations or interventions, length of bed rest (hours), length of hospitalization, length of activity restriction, time to urine cleared of blood, post discharge radiographic studies and findings, follow-up hemoglobin, blood pressure, and urinalysis for all follow-up visits, number of readmissions and reason for readmission, any post injury/post discharge complications and survival. 

Following hospital discharge, all patients will follow up in clinic with one of the investigators with urinalysis checks until the urine is clear and with blood pressure measurements. If the early blood pressures are normal, the patient will be followed every 6 months for 3 years. If hypertension is detected, the patient will be referred to nephrology for treatment and managed as indicated. The period of follow-up will be 3 years. The follow-up after the urine clears is for blood pressure measurements. Therefore, a blood pressure may be obtained by anyone in proximity to the patient as long as the results are sent to the investigators. This will ease the burden for the patients who don't live near the two hospitals.

Early vs. Delayed Operation for Perforated Appendicitis with Abscess

St. Peter, Shawn D.; Aguayo, Pablo; Fraser, Jason D.; Keckler, Scott J.; Sharp, Susan W.; Leys, Charles M.; Murphy, Patrick; Snyder, Charles L.; Sharp, Ronald J.; Andrews, Walter S.; Holcomb III, George W.; Ostlie, Daniel J. "Initial Laparoscopic Appendectomy vs. Initial Nonoperative Management and Interval Appendectomy for Perforated Appendicitis with Abscess: A Prospective, Randomized Trial." Journal of Pediatric Surgery. 45, (2010): 236-240.

Appendicitis is the most common surgical condition in children. Presentation varies widely. 

Some patients present after one-to-two weeks of perforation at which time a well-defined abscess is seen on the CT scan. These patients were historically treated with an immediate operation.

With the developing skill of interventional radiology, many institutions have been successfully treating this patient population with percutaneous drainage, intravenous antibiotics and interval appendectomy two months later. The proponents of delayed operation cite the ease of appendectomy with a very low complication rate.

Proponents of early operation argue that patients can be treated immediately, albeit with more operative difficulty and the patients completing therapy in five-to-seven days.

We are therefore comparing these two management strategies to determine which has more clinical advantages. Additionally, we are carefully measuring quality of life for the children and their parents during the three-month period of the study. Thirty patients will be enrolled in this pilot study.

Intravenous versus Intravenous-Oral Antibiotics for Perforated Appendicitis

Intravenous versus Intravenous-Oral Antibiotics for Perforated Appendicitis (Presented at the 2008 meeting of the American Academy of Pediatrics)

This is a single institution, prospective, randomized clinical trial involving patients who present to Children's Mercy Kansas City with perforated appendicitis. This will be a definitive study.

Power calculation was based on the abscess rate in our previously mentioned prospective study (Journal of Pediatric Surgery 43:981-985, 2008). Our current rate is 18% or just under one-fifth of the patients. A doubling of this rate to 36% would place just over one-third of the patients at risk, which would be unacceptable.

Using a delta of 0.18 with alpha of 0.05 and power of 0.8, the sample size is 74 patients in each arm. Therefore we will anticipate enrolling 150 patients. Sample calculation was performed with consultation from our hospital statistician, Dr. Steve Simon.

Subjects will be those children who undergo a laparoscopic appendectomy as part of their routine care. Perforation will be defined as an identifiable hole in the appendix or stool in the abdomen.

The control group will receive our current standard care for perforated appendicitis: ceftriaxone 50mg/kg once a day (maximum dose = 2 grams) and metronidazole 30mg/kg once a day (maximum dose = 1 gram). The length of antibiotic therapy will be a minimum of five days.

At that time, if the patient is afebrile for at least 24 hours, a white blood cell (WBC) count is obtained. If that is normal, the antibiotics are discontinued and the patient is discharged. If the WBC is elevated, they receive another two days before recheck. If still elevated, they receive another three days (10 days total) and a CT is obtained.

The experimental group receives the same combination of antibiotics while in the hospital. Whenever the patient is tolerating a regular diet, on oral pain medication and has been afebrile for more than 12 hours, they are discharged on oral antibiotics to complete a total seven-day antibiotic course. The home antibiotic regimen is ampicillin/clavulanic acid (Augmentin®). The Augmentin® dose will be 40mg/kg twice daily. The primary endpoint is the rate of abscess formation between the two groups.

Laparoscopic vs. Open Pyloromyotomy for Pyloric Stenosis

Laparoscopic vs. Open Pyloromyotomy for Pyloric Stenosis (St. Peter, S.D., Holcomb, G.W., Calkins C.M., Murphy J.P., Andrews, W.S., Sharp R.J., Snyder, C.L., Ostlie D.J., Open versus Laparoscopic Pyloromyotomy for Pyloric Stenosis: A Prospective, Randomized Trial. Presented at the 2006 meeting of the American Surgical Association. Annals of Surgery2006;244(3):363-70.)

This was a prospective randomized study involving infants less than three months of age with pyloric stenosis. 

Subjects with ultrasound-proven pyloric stenosis were randomized to either open or laparoscopic pyloromyotomy. Postoperative pain management, feeding schedule and discharge criteria were identical for both groups. Operating time; postoperative emesis; analgesia requirements; time to full feeding; length of hospitalization after operation; and complications were compared.

From April 2003 through March 2006, 200 infants were enrolled in the study. There were no significant differences in operating time, time to full feeding or length of postoperative hospitalization. There were significantly fewer number of emesis episodes and doses of analgesia given in the laparoscopic group. One mucosal perforation and one incisional hernia occurred in the open group.

Late in the study, one patient in the laparoscopic group was converted to the open operation. A wound infection occurred in four of the open patients compared to two of the laparoscopic patients (P = 0.68).

Conclusion: There is no difference in operating time or length of recovery between open and laparoscopic pyloromyotomy. However, the laparoscopic approach results in less postoperative pain and reduced postoperative emesis. In addition, there were fewer complications in the laparoscopic group. Finally, patients approached laparoscopically will likely display superior cosmetic outcomes with long-term follow-up.

Prospective Randomized Trial Evaluating the Utility of Esophageal Mobilization During Laparoscopic Fundoplication

St. Peter, Shawn D.; Bamhart, Douglas C.; Ostlie, Daniel J.; Tsao, KuoJen; Leys, Charles M.; Sharp, Susan M.; Bartle, Donna; Morgan, Tracey; Harmon, Carroll M.; Georgeson, Keith E.; Holcomb III, George W. "Minimal vs Extensive Esophageal Mobilization During Laparoscopic Fundoplication: A Prospective Randomized Trial." Journal of Pediatric Surgery. 46, (2011): 163-168.

This is a two-center, prospective randomized clinical trial involving patients who require an operation for gastroesophageal reflux disease. This is intended to be a definitive study. All patients will receive the standard operation for GE reflux: laparoscopic Nissen fundoplication.

There is controversy as to whether the esophagus should be mobilized extensively in the abdomen. Also, from our retrospective data, there appears to be an increased (12% vs. 5%) incidence of transmigration of the fundoplication wrap if the esophagus is extensively mobilized (J Pediatr Surg 42:25-30, 2007).

Sample size calculated on a power of 80% with an alpha level of 0.05 using the recurrence rates demonstrated by our retrospective data produce the number of 159 patients in each arm of the study. Given that we will need to follow these patients for one year after enrollment, there may be some attrition due to lost follow-up. Therefore, 180 patients per arm would allow for just over 10% attrition.

One group undergoes laparoscopic fundoplication with complete mobilization of the lower esophagus by circumferentially dividing the phrenoesophageal membrane. The other group undergoes laparoscopic fundoplication without dividing this membrane. In both groups, four esophagocrural sutures are placed to secure the esophagus in the abdomen (see the above-mentioned report in the Journal of Pediatric Surgery). The operation, postoperative care and follow-up plan will otherwise not differ between groups.

If four consecutive recurrences are found in one group, an interim analysis will be conducted. If a recurrence difference of statistical significance between groups is detected, the study will be concluded at this point. Without these occurrences, an interim analysis will be conducted after 180 patients have been enrolled. The primary endpoint is the incidence of wrap transmigration.

Prospective Randomized Evaluation of Antibiotic Regimens Following Appendectomy for Perforated Appendicitis

Single Daily Dosing Ceftriaxone and Metronidazole vs Standard Triple Antibiotic Regimen for Perforated Appendicitis in Children: A Prospective Randomized Trial (Shawn D. St. Peter, Kuojen Tsao, Troy L. Spilde, George W. Holcomb III, Susan W. Sharp, J. Patrick Murphy, Charles L. Snyder, Ronald J. Sharp, Walter S. Andrews, Daniel J. Ostlie) Journal of Pediatric Surgery 2008;43:981-985.

A retrospective review at Children's Mercy Kansas City found ceftriaxone and metronidazole (CM) to be a more simple and cost-effective antibiotic strategy than traditional triple antibiotic therapy (ampicillin, gentamicin, clindamycin; AGC) for perforated appendicitis. Therefore, we performed a prospective, randomized trial to compare efficacy and cost-effectiveness of these two regimens.

Children found to have perforated appendicitis at appendectomy were randomized to either once daily dosing of CM (two total doses/day) or standard dosing of AGC (11 total doses/day). Perforation was defined as an identifiable hole in the appendix or stool in the abdomen.

The operative approach (laparoscopic), length of antibiotic usage and criteria for discharge were standardized for the groups. Based on our retrospective analysis using length of postoperative hospitalization as a primary endpoint, a sample size of 100 patients was calculated for an alpha of 0.5 and a power of 0.82. Thus, 100 patients were enrolled. One case was converted to an open operation. Two patients were excluded, one due to surgical failure (retained fecalith) and the other due to transfer to another hospital prior to completion of the antibiotic course. On presentation, there were no differences in gender distribution, days of symptoms, temperature or leukocyte counts between the two groups.

Conclusion: There was no difference in time to regular diet, length of hospitalization, percentage of postoperative abscess or percentage of wound infection. The antibiotic charges, however, were dramatically higher in the three-drug regimen (P < 0.001). Therefore, once daily dosing with the two drug regimen (CM) was found to offer a more efficient, cost-effective antibiotic management in children with perforated appendicitis without compromising infection control when compared to a traditional three-drug regimen.

Thoracoscopy versus Fibrinolysis in Children with Empyema

Thoracoscopic Decortication vs Tube Thoracostomy with Fibrinolysis for Empyema in Children: A Prospective, Randomized Trial (Shawn D. St. Peter, Kuojen Tsao, Christopher Harrison, Mary Ann Jackson,Troy L. Spilde, Scott J. Keckler, Susan W. Sharp, Walter S. Andrews, George W. Holcomb III, Daniel J. Ostlie) Journal of Pediatric Surgery 2008;44:106-111.

This was a single institution, prospective, randomized clinical trial involving patients who are found to have one or more septations within a pleural effusion as diagnosed by ultrasound or computed tomography. Additionally, patients with a pleural effusion wherein a pleural tap reveals pus, as defined by many (>10,000/mm³ ) white blood cells or positive cultures, will be considered. This is intended to be a definitive study.

Based on our retrospective data using length of postoperative hospitalization, a sample size of 36 patients was calculated with an alpha of 0.5 and a power of 0.8. Video-assisted thoracoscopic debridement (VATS) were performed in standard fashion with chest tube left behind after the operation. Fibrinolysis consisted of inserting a 12 Fr chest tube followed by infusion of 4mg tPA mixed in 40 ml of normal saline at the time of tube placement followed by two subsequent doses 24 hours apart.

At diagnosis, there were no differences between groups in age, weight, degree of oxygen support, WBC count or days of symptoms. Outcomes showed no difference in length of hospitalization, days of oxygen support, days with a fever or number of analgesic doses.

The procedure charges were significantly higher in the VATS group. Three patients (16.6%) in the fibrinolysis arm required VATS for definitive therapy. Two patients in the VATS group required ventilator support after therapy, one of which required temporary dialysis. No patients in the fibrinolysis group clinically worsened after initiation of therapy.

Conclusions: There are no therapeutic or recovery advantages between VATS and fibrinolysis for the treatment of empyema. However, VATS resulted in significantly greater charges. Fibrinolysis should be considered the first line therapy for children with empyema.