From the late nineteenth century on, when William Stewart Halsted introduced the concept of surgery as a viable academic discipline, surgical research has been responsible for ongoing advancements in patient care (4,5). Since this time, the cornerstone of clinical research in surgery has been observation only (6,7). Observation begins with careful assessment of the results of one’s own outcomes in his or her patients and extends to the “case-series” study that is currently the backbone of clinical research in surgery (8,9).

Observational studies have provided much valuable information advancing the cause of patient care. However, overreliance on the results of these studies to the exclusion of applying more scientifically rigorous methods has also allowed ineffective and even harmful treatments to persist for many years. Barnes reviewed an extensive series of surgical procedures that were supported by published observational studies, but that were subsequently found to be ineffective and were abandoned (10). A modern example of a procedure widely supported by observational studies until subjected to rigorous scientific inquiry is the extracranial-intracranial bypass operation. This operation was shown in many different observational studies to reduce stroke risk over medical therapy for intracranial carotid disease (11,12). A subsequent randomized controlled trial showed it to be ineffective, and that bias in the observational studies had led to the wrong conclusion and subsequently the wrong therapy for many patients (13). The evolution of
breast cancer therapy in the United States provides an example of how rigorous scientific inquiry can dramatically alter a previously accepted approach to surgical disease (14,15,16). Prospective randomized clinical trials have resulted in significant advances in the surgical management of carotid artery disease, adenocarcinoma of the colon, and many other diseases (17,18,19,20,21). Despite the dramatic impact of these studies on surgical care, the application of rigorous scientific inquiry to clinical questions in surgery remains the exception rather than the rule (22,23,24).

To date, clinical research in pediatric surgery has been comprised predominantly of retrospective nonrandomized observational studies. The most comprehensive review of the subject was undertaken by Hardin et. al. in 1999 (25). These investigators reviewed and categorized more than 9,000 manuscripts in the major pediatric surgical journals during a 22-year period (Fig. 5-1). When basic laboratory studies (11.8% of the total) were excluded, 97.5% of all studies were either case reports or single institution case series studies. Prospective studies were infrequently performed and randomized controlled trials (RCTs) were rare. Moss et. al. focused on the use of RCTs in pediatric surgery and found that only 0.17% of more than 80,000 studies in the field were clinical trials (26). Furthermore, the majority of these RCTs suffered from major design and execution flaws, and most did not directly study surgical therapy (Table 5-1). Thakur and colleagues confirmed that most pediatric surgical studies are observational, and reported finding serious methodological defects in both randomized and nonrandomized studies (27).

Why is there a paucity of high-quality evidence in pediatric surgery? Rangel et. al. identified several barriers impeding the widespread use of randomized trials and other high-quality prospective studies in pediatric surgery:

There is no question that conducting the rigorous clinical studies necessary to generate high-quality evidence in pediatric surgery is rarely possible at a single institution. Even the largest children’s hospitals do not have sufficient numbers of patients to study most of the important clinical questions. In other disciplines where the study of infrequent diseases is common, the use of multicenter collaborative study groups have been employed to generate the necessary sample size for meaningful scientific inquiry. The success of the cooperative Children’s Oncology Group is testament to this (28,29). Through large cooperative trials, this group has accomplished a dramatic increase in survival for children with cancer. Perhaps the most notable accomplishment is a 70% decrease in mortality from childhood acute lymphocytic leukemia without the development of a single new chemotherapeutic agent (30). This advance occurred by the careful modification of existing therapeutic regimens based on the results of rigorous multicenter randomized clinical trials. In the United States, 78% of children with cancer are currently enrolled in a clinical trial (31). This is in stark contrast to our own field, where less than 0.1% of children undergoing major surgical procedures are enrolled in a trial (26). The recent success of the Cystic Fibrosis Therapeutics Development Network provides an additional example of a consortium’s effectiveness at accomplishing research advancing care for an uncommon disease (32,33).

The development of large-scale cooperative groups such as those mentioned previously requires significant financial resources. This is a particular challenge in pediatric surgery. Studies have shown that the National Institutes of Health (NIH) is less likely to fund clinical compared with basic research, and surgical compared with nonsurgical research (34,35). The difficulty in obtaining funding for research in uncommon diseases is well documented (36). To obtain funding for infrastructure, cooperative groups typically must demonstrate a track record of success. However, one of the key elements required for success is adequate infrastructure. For small disciplines such as pediatric surgery, these issues can be prohibitive.

Obtaining the state of equipoise in the surgical community necessary to conduct rigorous clinical research is challenging. Equipoise is defined as “a state of mind characterized by legitimate uncertainty or indecision as to choice or course of action because of a balance of potential gains versus losses or of benefits versus risks” (37,38,39). The difficulty in obtaining equipoise in the pediatric surgical community stems from two factors. First, there is a long-standing tradition of basing therapeutic decisions on the results of observational data (40). Second, although indecision is fundamental to evaluating the absence of available evidence for a treatment plan, indecision with respect to management of an individual patient or with respect to an intraoperative decision is counterproductive and decidedly nonsurgical (30). Surgeons committed to evidence-based practice face the challenge of maintaining intellectual equipoise with respect to evaluating therapies, while maintaining the decisiveness necessary to be an effective surgeon (41).

Clinical research involving surgical therapy presents unique challenges to the design and conduct of clinical studies. Blinding of patients and surgeons to treatment assignments is often impossible. Furthermore, the well-documented placebo effect of surgical treatment can present challenges in detecting the true benefits of novel interventions (42,43). Nevertheless, effective randomization can still be achieved, and blinding of study personnel during the procurement and analysis of outcomes data is possible even for surgical interventions. Standardization of surgical procedures is essential to the validity of clinical research studies. This challenge may be overcome by establishing standardized training centers, or by disseminating study protocols of operative technique over the Internet (44,45).

The final issue of the willingness of health care providers to randomize their patients is one of individual leadership and intent. In contrast to trials investigating nonoperative therapy, surgical trials are associated with interventions that are irreversible and potentially disfiguring. In this regard, parents may be very reluctant to randomize their children into trials with potentially invasive treatment arms. Nevertheless, with a thoughtful, compassionate, and well-informing presentation of the study to patients by their physicians, enrollment can be maximized (46,47). Nurses have an enormous opportunity for leadership in this regard because they are often the first line of contact in helping patients and their families understand the benefits of clinical trials to an individual patient and to advancement of medical knowledge (48,49).