A Retrospective Identification of Gastroesophageal Reflux Disease as a New Risk Factor for Surgical Site Infection in Cerebral Palsy Patients After Spine Surgery

Chidambaran, Vidya MD*; Gentry, Carol RN; Ajuba-Iwuji, Chinwe MD; Sponsellar, Paul D. MD, MBA§; Ain, Michael MD§; Lin, Elaina MD; Zhang, Xue PhD; Klaus, Sybil Ann MD#; Njoku, Dolores B. MD‡#

Anesthesia & Analgesia:
doi: 10.1213/ANE.0b013e318290c542
Pediatric Anesthesiology: Research Report

BACKGROUND: Neuromuscular scoliosis is a known risk factor for surgical site infection (SSI) after spinal fusion, with reported infection rates as high as 11.2%. Although risk factors such as antibiotic timing have been previously addressed, our objective was to identify intrinsic risk factors for SSI in cerebral palsy (CP) patients with neuromuscular scoliosis. We hypothesized that CP patients who develop SSI after spine fusion would have a risk profile similar to those who develop nosocomial infection.

METHODS: We retrospectively analyzed records from patients with CP who developed infections after spinal fusion from January 1998 until July 2008, who were identified by our Infection Control Officer using National Nosocomial Infection Surveillance System criteria (N = 34). Demographically and procedurally matched controls without infection were identified from our spine database (N = 37). We compared these groups for gastroesophageal reflux disease (GERD), use of gastric acid inhibitors, presence of preoperative decubitus ulcer, previous infection, and postoperative ventilation. Multivariable logistic regression was then performed to assess the relative contributions of the predictors to “deep infection” and “any infection.”

RESULTS: Of 30 evaluable infected patients, 70% had incisional SSI. Although many of the infections were polymicrobial, the most common pathogens identified were Gram-negative bacilli. Many significant predictors were identified by univariable logistic regression for any infection and deep infection. Multivariable logistic regression found a significant effect only for GERD (odds ratio, 6.4; 95% confidence interval, 1.9–21.3; P = 0.002) for any infection, whereas the effect of therapy with gastric acid inhibitors did not reach statistical significance (odds ratio, 6.1 [95% confidence interval, 0.84–44.6]; P = 0.07). No significant interaction between the 2 factors was detected. Among our controls and infected patients altogether, 46.3% had GERD.

CONCLUSIONS: We show that GERD increases the risk for infection in CP patients after spine fusion. Prospective multicenter studies are necessary to further validate the predictive value of this risk factor.

In Brief

Published ahead of print May 17, 2013

Author Information

From the *Department of Pediatric Anesthesia, Cincinnati Children’s Hospital, University of Cincinnati, Cincinnati, Ohio; Department of Perioperatve Services, Johns Hopkins University; Departments of Anesthesiology and Critical Care Medicine and §Orthopedic Surgery, the Charlotte R. Bloomberg Children’s Center, Johns Hopkins University, Baltimore, Maryland; Department of Anesthesiology and critical care, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Biostatistics and Epidemiology, University of Cincinnati, Cincinnati, Ohio; and #Department of Pediatrics, the Charlotte R. Bloomberg Children’s Center, Johns Hopkins University, Baltimore, Maryland.

Accepted for publication February 21, 2013

Published ahead of print May 17, 2013

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Dolores B. Njoku, MD, Department of Anesthesiology and Critical Care Medicine, the Charlotte R. Bloomberg Children’s Center, Johns Hopkins University, 800 Orleans St., Room 6349D, Baltimore, MD 21287. Address e-mail to dnjoku@jhmi.edu.

Article Outline

Neuromuscular scoliosis is a known predisposing condition for postoperative infection after spine fusion.1 This type of scoliosis describes any patient with a disorder of the neurologic system such as myelomeningocele, muscular dystrophy, or cerebral palsy (CP) who also has a lateral curvature of the spine with a Cobb angle of >10°. The prevalence of neuromuscular scoliosis in CP patients ranges from 20% to 60% with higher rates occurring in nonambulatory patients.2 In this group of patients, spine curvature begins at a younger age and is more likely to fail conservative interventions.2 Surgical intervention is often necessary with the potential for numerous complications.3

Surgical site infection (SSI) is a serious complication of spinal fusion often requiring prolonged antibiotic administration and reoperation. Despite advances in surgical techniques and prophylactic antibiotics, reported rates of postoperative infection in CP patients remain unacceptably high (6.1%–15.2%) when compared with 0.5% to 6.7% in patients with idiopathic scoliosis.4–7 While the mechanisms responsible for this predisposition are not completely clear, prior studies suggest that CP patients represent a high-risk category because of their nutritional status, diminished mobility, and urinary or fecal incontinence.2,8 Instrumentation, ventriculoperitoneal shunts, and colonization with enteric bacteria have also been identified as predisposing factors for postoperative infection.9,10

Prior studies have identified risk factors specific to nosocomial infection in children;11,12 however, these factors have never been investigated as risk factors for SSI after spine fusion. These landmark studies clearly show that gastroesophageal reflux disease (GERD) increases the risk of respiratory disorders in children without neurologic deficits, and that gastroenteritis and community-acquired pneumonia when combined with gastric acid inhibitors increase the risk of respiratory disorders.13–15 Additionally, several observational studies have found correlations between hyperglycemia and increased mortality, length of stay, and infection in children.16,17

Our objective was to identify intrinsic risk factors for SSI in CP patients with neuromuscular scoliosis. We hypothesized that patients with CP who develop SSI after spine fusion have a risk profile similar to those who develop nosocomial infection, including a history of GERD, use of gastric acid inhibitors, presence of preoperative decubitus ulcer, previous infection, and postoperative ventilation. To our knowledge, no prior study has demonstrated an association between risk factors for nosocomial infections and postoperative SSI after spinal fusion. Understanding preoperative risk factors may diminish infectious complications through focused interventions by the health care team.

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This retrospective, matched, case-control study was exempted by our IRB, and requirement for written consent waived. National Nosocomial Infection Surveillance System definitions were applied for identifying SSI.18 Incisional SSIs were defined as occurring within 30 days after surgery and divided into superficial (involving only skin and subcutaneous tissue) and deep (involving deeper soft tissues of the incision if no implant was left in place or within 1 year if implant was in place). Organ-space SSIs were defined as those involving any part of the anatomy other than incised body wall layers that were opened or manipulated during an operation. Patients developing other infections such as pneumonia, urinary tract infections, and bacteremia were also included in this category. SSI had to meet at least 1 of the following criteria: (1) purulent drainage with or without laboratory confirmation, (2) isolation of organisms from aseptically obtained cultures of fluid or tissue, (3) signs or symptoms of infection, which include pain/tenderness, localized swelling, redness, or heat, (4) incisions deliberately opened by the surgeon and culture positive, and (5) diagnosis by the surgeon or other attending physician. As deep incisional SSIs are associated with higher morbidity, we separated our analysis into 2 separate outcomes: (1) deep infection, defined as deep incisional SSI only, and (2) any infection, which was defined as superficial, deep, or organ-space SSI.

Two experienced pediatric orthopedic spine surgeons performed all surgeries. Patients who developed infection after spinal fusion between January 1998 and July 2008 were identified by our Infection Control Officer (N = 34). As all patients were diagnosed with CP and ASA status 3, we selected demographically and procedurally matched CP patients with scoliosis >55° who did not develop postoperative infection (N = 37) to function as the control group from our database of 665 pediatric patients who underwent spinal fusion during the study period at our institution. Control and infected groups were matched for the following: age, weight, sex, etiology of scoliosis, Cobb angle, surgical procedure, and duration. Information regarding history of GERD, prior Nissen/gastrostomy tube, preoperative medications, previous postoperative infections after an unrelated surgery, congenital syndromes, and decubitus ulcers were obtained from review of patient medical records. Weight-adjusted blood loss and volume of crystalloid or blood products administered intraoperatively were also recorded. Glucose levels measured before, during, and after surgery after admission to the intensive care unit or floor were noted. Maximal glucose levels within 7 days of surgery were also evaluated. The duration of intubation, incidence and details of infection, along with the organisms cultured were also recorded.

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Statistical Analysis

To identify potential predictors for SSI and infection, we first assessed the effect of history of GERD, use of gastric acid inhibitors, presence of preoperative decubitus ulcer, history of infection, and postoperative ventilation on occurrence of “deep infection” and “any infection” using univariable bias-reduction logistic regression models (the Firth algorithm). These variables were then tested in multivariable models, and excluded from the final models if inclusion did not show significant effects (P > 0.05). The effects of age, sex, or weight were tested in each of the models, and no significant effects were detected. As 2 major multivariable regressions were conducted, we set the significance level at 0.025 after Bonferroni correction. Analyses were performed using Statistical Analysis Software, version 9.3 (SAS Institute Inc., Cary, NC). The SAS procedure is Proc logistic; Model y = x/firth; Run. Comparison of the control and infected groups for categoric and continuous variables was done using the Fisher exact test and the 2-sample t test, respectively, using GraphPad Prism version 5.03 for Windows (GraphPad Software, San Diego, CA).

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Demographic Data Were Similar Between Control and Infected Groups

The overall incidence of infection for the study period was 8.3%. Thirty-four CP patients developed infections after spinal fusion from January 1998 until July 2008. Four patients were excluded: 1 was 54 years old, and the other 3 had experienced cardiac arrest during surgery. Demographically and procedurally matched controls without infection (N = 37) were obtained from our pediatric spine database, as specified in Methods. As they were matched for age, weight, sex, etiology of scoliosis, Cobb angle, surgical procedure, and duration, we confirmed that the 2 groups did not show significant differences when compared for those factors and ASA status (Table 1). No significant difference in incidence of congenital syndromes, ASA status, and antibiotic compliance was detected between control and infected groups (Table 1). One patient in the infected group had a diagnosis of Morquio syndrome and 2 patients in the control group had CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genitourinary defects [hypogonadism], Ear problems [or deafness]) or Prader-Willi (Table 1).

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The Majority of Infected Patients Had Incisional SSIs

Seventy percent of infected patients had incisional SSI (21/30; Fig. 1A). Of these, 11 patients (52%) met criteria for deep SSI, and 10 patients (48%) had superficial SSI. Two patients with deep infection and 2 patients with superficial infection required surgical debridement. Four other patients with deep SSI required revision or removal of instrumentation. Among patients who developed deep SSI, 4 patients had a total of 6 concurrent organ-space infections (2 pneumonia, 2 bacteremia, 1 infected ventriculoperitoneal shunt, and 1 infected sacral ulcer). Thirty percent of infected patients were diagnosed with solely organ-space infection: pneumonia (n = 4), bacteremia (n = 2), urinary tract infection (n = 2), and infected decubitus ulcer (n = 1).

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Gram-Negative Bacilli Were Cultured in the Majority of Infected Patients

Cultures were positive in 50% of the infected cases. Gram-negative bacilli (GNB) including Pseudomonas, Enterococcus, and Enterobacter species comprised 70% of the organisms isolated from surgical sites, sputum, blood, or urine cultures. Anaerobic species (Bacteroides) and Gram-positive bacteria (Staphylococcus aureus [SA] and Streptococcus) each comprised an additional 15% (Fig. 1B). Staphylococcus was the predominant organism in superficial infections. The same organisms were cultured at the deep SSI site as in the blood and other organ sites in those who developed concurrent bacteremia (methicillin-sensitive SA and Enterobacter) and shunt infection (Pseudomonas).

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GERD Combined with Ranitidine Therapy Was Significantly Higher in Infected Patients

Among our controls and infected patients altogether, 46.3% had GERD. The prevalence of GERD was significantly higher in the infected (66%) when compared with the control (23%) group. Forty percent of patients in the infected group received therapy with gastric acid inhibitors, the overwhelming majority being treated with ranitidine. Two patients received omeprazole, whereas 1 received lansoprazole. Of the 4 patients with serious infections necessitating hardware removal, 100% of these patients were diagnosed with GERD and were receiving gastric acid inhibitors. As a comparison, 23% of the controls were diagnosed with GERD, and only 1 patient (3%) was being treated with ranitidine. The risk of any infection and deep infection in patients with GERD and in patients treated with gastric acid inhibitors were statistically significant using univariate analysis and are shown in Table 2. These findings strongly suggested that GERD and treatment with ranitidine increased risk for SSI in CP patients. In support of our findings, 33% of the infected patients had prior Nissen and gastrostomy tube placement when compared with 5.7% in the control group. Moreover, the Fisher exact test showed that having a prior Nissen/gastrostomy tube procedure significantly increased the risk for SSI (odds ratio [OR] 8 [95% confidence interval {CI}, 1.6–40.6]; P = 0.0085). Multivariable logistic regression detected weak effects of GERD (P = 0.06) and treatment with gastric acid inhibitors (P = 0.07) on occurrence of deep infection. For any infection, a significant effect of GERD was detected (OR 6.4 [95% CI, 1.9–21.3]; P = 0.002), but was only weak for therapy with gastric acid inhibitors (OR 6.1 [95% CI, 0.84–44.6]; P = 0.07). We did not find a significant interaction between GERD and therapy by testing for interaction in the multivariate model.

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Prior Surgical Infection Increased the Risk for Postoperative Infections After Spine Fusion

Although both groups had similar histories of unrelated surgeries, a higher proportion of the patients in the infected group had a history of postoperative infections with prior surgeries (43% [infected] vs 0.05% [control]). ORs and P-values for this factor calculated for “any infection” and “deep infection” are presented in Tables 2 and 3.

Surgical times were comparable between groups (P = 0.48). The number of patients undergoing a concomitant procedure was higher in the infected group (P = 0.04). To address antibiotic compliance, we confirmed that all patients received antibiotics (cefazolin 25 mg/kg; some also received gentamycin 1.5 mg/kg) within an hour before incision and cefazolin was repeated every 3 hours intraoperatively. IV fluid administration during spine fusion was different between study groups but not found statistically significant (Table 4). Estimated blood loss and packed red blood cells administered were similar between study groups, when normalized to weight (Table 4). There was no difference in preoperative, intraoperative, immediate postoperative, or 7-day postoperative maximum glucose levels between infected and control groups (Table 4). However, when comparing these time points within control and infected groups, there was a significant increase in glucose levels at all other time points, when compared with preoperative values (P < 0.0001). Last, we assessed study groups for the prevalence of postoperative mechanical ventilation because this had previously been reported to increase the risk for nosocomial infection. Seventeen infected patients and 15 controls required mechanical ventilation for at least 12 hours after surgery. Univariable logistic regression showed that the odds for developing SSI were increased between groups but not for deep infection (Tables 2 and 3).

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We have conducted a retrospective, matched, case-control study of CP patients with postoperative infection after spine surgery. We have identified multiple risk factors for postsurgical infection, including prior surgical infection, presence of GERD, and therapy with gastric acid inhibitors using univariate analysis; in subsequent multivariable analysis, only GERD remains a significant factor. We conclude that identification of preoperative risk factors for infection could facilitate studies to evaluate whether risk monitoring and interventions may alter perioperative morbidity.

Neuromuscular scoliosis is a known risk factor for SSI after spine surgery. Surgical duration or approach, residual Cobb angle, ASA score >2, obesity, and antibiotic prophylaxis with clindamycin have all been identified as independent risk factors for SSI.1,5,19,20 Surgical duration, approach, and Cobb angle were controlled for in this study as the groups were matched for these risk factors and hence, were not significantly different among the groups. However, all surgeries were performed by only 2 surgeons, which may have reduced variability in these risk factors. There was no significant difference with respect to ASA scores and antibiotic compliance among the infected and control groups.

Using univariate analysis, history of infection, GERD, and therapy with gastric acid inhibitors are identified as risk factors for postoperative SSI in CP children after spine fusion, suggesting that there may be an innate susceptibility to infection in some CP patients who develop SSI after spine fusion. GERD remains a significant factor after multivariate regression, suggesting a strong impact of GERD in our cohort.

It is interesting to note that CP patients have up to 50% incidence of GERD.21 Many of them are taking histamine-2 blockers and proton pump inhibitors. GERD increases the risk of respiratory infectious processes in children without neurologic deficits.15 Histamine-2 blockers and proton pump inhibitors have also been associated with an increased risk of acute gastroenteritis, community-acquired pneumonia, and ventilator-associated pneumonia; however, they have never been previously identified as risk factors for postoperative infections.13,14,22

Prior studies may help explain the link between GERD, gastric acid inhibitors, and postoperative infection. First, GERD may predispose to suboptimal nutrition and aspiration pneumonia. Second, patients with GERD treated with acid inhibitors lose the protective acid barrier of the stomach increasing the risk for bacterial overgrowth.23 Gastric pH >4 supports overgrowth of GNB,24 which may promote pulmonary infections.25 Bacterial overgrowth also markedly increases the luminal concentration of bile acids that may support bacterial translocation and bacteremia.26 Third, gastric acid inhibitors directly inhibit several leukocyte functions27 and modify gastrointestinal microflora quality and quantity.28 Spinal instrumentation may act as a nidus for the translocated bacteria. Perineal colonization with Gram-negative flora, a risk factor in patients with incontinence and incisions extending to the sacral region, may augment contributions by GERD; however, bacterial translocation has not previously been associated with this process.29

SSI in spine fusion is commonly polymicrobial.30,31 Our data are consistent with these findings as GNB are responsible for 70% of cultured microorganisms, in addition to Staphylococci and anaerobes. It is interesting to note that we report Gram-negative aerobic bacteria in most of our positive cultures, instead of SA as previously reported.9 Thus, each institution may need to identify their likely organisms and streamline antibiotics to target these organisms. Our study numbers were too low to draw complete conclusions, but our findings may have suggested that antibiotic regimens specific for enteric organisms may have been beneficial in this population. We used 25 mg/kg cefazolin. There were no universally established recommendations for prophylactic antibiotic dosing for pediatric spine surgeries. The practices at most institutions suggested that 25 to 40 mg/kg cefazolin is the recommended dose. Although higher doses such as 40 to 50 mg/kg cefazolin were used at other institutions, at the time of the study there was no accepted evidence that the higher dose prevented SSI better than the lower doses. Hence, our dose of 25 mg/kg cefazolin was within the acceptable recommendations for antibiotic prophylaxis.

Differences in intraoperative fluid administered did not reach statistical significance. Control patients received approximately 2 times more crystalloid than infected patients, possibly resulting in improved tissue perfusion, better tissue levels of antibiotics, and reduced risk for bacterial growth. Postoperative ventilation as a risk factor for infection may be a surrogate marker for more involved surgery or sicker, more debilitated patients, although the controls and infected cases were matched for ASA status and duration/type of surgery. Elevated glucose levels and diabetes are independent risk factors for infection after spine surgeries in adults.32 Hence, we expected similar results in children. However, we do not show significant differences in glucose values in the perioperative period between study groups. We did find significant differences in glucose levels at the different time points when compared with baseline values within study groups. Thus, our findings suggest to us that mechanisms of hyperglycemia in high-risk pediatric patients may differ from adults33 and may be a normal response.

Despite our exhaustive list of potential variables, our results are limited by the drawbacks associated with retrospective studies, namely, reliance on written records, missing data, and inability to use randomization. GERD was diagnosed by gastroenterologists or other physicians, and endoscopic confirmation was not always documented. Intraoperative temperature was not documented on many charts, especially in the earlier dates, making it difficult to assess association of infection risk with hypothermia. However, in a retrospective case-control study to identify risk factors associated with SSI after pediatric posterior spine fusion, hypothermia during surgery was found to provide protection against SSI in this patient population.20 Fraction of inspired oxygen (FIO2) was documented in our paper records as either a percentage or ratio of flow mixed with either air or nitrous oxide. Levels of oxygen used in either control or infected groups ranged from 60% to 100%. FIO2 was not analyzed because the evidence for the protective effect of hyperoxia against infection is still controversial and is better documented for abdominal surgeries.34 Moreover, we cannot exclude the possibility that we missed important risk factors for infection by using strict criteria and comorbidity-matched single CP controls. We would also like to point out that 1 feature of our data set is high correlation among predictors (e.g., the r value for correlation between gastric acid suppressant usage and GERD is 0.42, and the r value between gastric acid suppressant usage and previous infection is 0.40). When independent variables are highly correlated, it becomes difficult to determine their individual impact on the dependent variable when they are tested in 1 model. Although it does not reduce reliability of the model as a whole, it may not give reliable estimates for each individual predictor. Therefore, to avoid overinterpretation of the multivariate analysis, only GERD that is the consistent variable detected by multivariate analysis and the relevant gastric acid suppressant tested in the final multivariate model are presented in this article. The wide range of the values for 95% CI may mean that the findings lack precision and represent an overassociation versus a true association, likely due to the small sample size.

We conclude that GERD is a novel risk factor for infection after spine surgery in patients with CP. We show for the first time that some risk factors for nosocomial infection in children without chronic disease may also increase the risk for SSI in CP patients. We suggest that our findings may also be relevant to other populations with similar risk factors undergoing other surgeries involving instrumentation. Larger prospective studies will be needed to validate our findings.

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Name: Vidya Chidambaran, MD.

Contribution: This author helped with the study design, conduct of the study, data analysis, and manuscript preparation.

Attestation: This author approved the final manuscript.

Name: Carol Gentry, RN.

Contribution: This author helped with the study design and conduct of the study.

Attestation: This author approved the final manuscript.

Name: Chinwe Ajuba-Iwuji, MD.

Contribution: This author helped with the data analysis and manuscript preparation.

Attestation: This author approved the final manuscript.

Name: Paul D. Sponsellar, MD, MBA.

Contribution: This author helped with the study design and conduct of the study.

Attestation: This author approved the final manuscript.

Name: Michael Ain, MD.

Contribution: This author was responsible for the conduct of the study.

Attestation: This author approved the final manuscript.

Name: Elaina Lin, MD.

Contribution: This author helped with the study design, data analysis, conduct of the study, and manuscript preparation.

Attestation: This author approved the final manuscript.

Name: Xue Zhang, PhD.

Contribution: This author helped with the data analysis.

Attestation: This author approved the final manuscript.

Name: Sybil Ann Klaus, MD.

Contribution: This author helped with the data analysis.

Attestation: This author approved the final manuscript.

Name: Dolores B. Njoku, MD.

Contribution: This author helped with the study design, conduct of the study, data analysis, and manuscript preparation.

Attestation: This author approved the final manuscript.

This manuscript was handled by: Peter J. Davis, MD.

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