Application of Network Meta-Analysis to Assess the Comparative Effectiveness of Oral Care Interventions in Preventing Ventilator Associated Pneumonia in Critically Ill Patients.

Abstract

Background In this research, we assessed the efficacy of a novel analytic, network metanalysis (NMA), in creating a hierarchy to define the most effective oral care intervention (OCI) for the prevention and management of ventilation-associated pneumonia (VAP).

Methods We applied NMA to a previously published robust pairwise meta-analysis (PMA). Statistical analyses were based on comparing rates of total VAP events between intervention groups and placebo-usual care groups. We synthesized a netgraph, reported ranking order of the treatment and summarized our output by a forest plot with a reference treatment placebo/usual care.

Results With our inclusion and exclusion critiera for the NMA we extracted 25 studies (4473 subjects). The NMA included 16 treatments, 29 pairwise comparisons and 15 designs. Based on the results of multiple comparisons with frequentist ranking probability P scores, tooth brushing (P score fixed of 0.9353, P score random of 0.8892), toothbrushing with povidone iodine (P score fixed of 0.9091, P score random 0.8801), and furacillin (P score fixed of 0.8798, P score random 0.8358) were the best three interventions for preventing VAP.

Conclusion NMA appeared to be an effective platform from which multiple interventions reported in disparate clinical trials could be compared to derive a hierarchical assessment of efficacy in the intervention of VAP. According to the NMA outcome, toothbrushing alone or toothbrushing along with a potent antiseptic mouthwash povidone iodine was related to the highest response rate in preventing VAP in critically ill patients followed by furacillin and chlorhexidine 0.2%, respectively.

Background

Oral care interventions (OCI) have been recognized as favorably impacting the risk and course of ventilator-associated pneumonia (VAP) in critically ill patients. [1] A range of preventive strategies have been suggested that include the use of topical (rinse) formulations of antimicrobial agents, such as chlorhexidine (CHX) and povidone iodine (PI), and/or mechanical cleansing by healthcare providers. [1–4] Debate persists as to which tactic is most clinically- and cost-effective. A number of randomized trials (RCTs) have been completed to address this uncertainty. [4] In almost all cases, these RCTs have used a standard clinical trial pairwise design in which a placebo or best care was compared to a test agent or regimen. While this approach provides snapshot outcomes for a specific intervention, it lacks the ability to hierarchically assess or rank the efficacy of each in the context of all of the interventions studied.

To address this deficiency, we explored the utility of a novel approach in which network meta-analysis (NMA) was applied to a previously published comprehensive pairwise meta-analysis (PMA). [5] NMA, also known as multiple treatment comparison or mixed treatment comparison, is a method of generalization of conventional pairwise meta-analysis whereby the network statistically combines direct and indirect evidence from trials [7] to yield inter-study intervention comparisons. In addition, NMA expresses relative effectiveness of interventions among all trials and then rank orders them. We explored the utility of NMA as a means of comparing different OCIs with the objective of identifying those most effective for mitigating VAP in critically ill patients.

Concepts Of Network Meta-analysis

For clinical trials, conventional PMA typically focus on pairwise comparisons of an active treatment vs. a placebo or usual care with the objective of assessing superiority of the test agent vs. a control. If the investigation seeks to compare multiple active agents simultaneously, the sample size must increase leading to extended accrual times, extraordinary expense and efficacy assessment challenges.

In contrast NMA utilizes a multiple comparison methodology which enables the interventions of one trial to be contrasted with the active interventions of other trials, while maintaining the internal randomization of the direct and indirect comparisons. [figure 1]. For example, when two active OCIs like chlorhexidine ( CHX) and Toothbrushing (Tb) are independently compared for efficacy against a saline control in two different trials then randomised comparison in the trial 1, CHX and saline provides a direct estimate of the treatment effects of CHX and Saline, measured on the scale as log odds ratio. We then denote this approach as θ _{CHX Saline} ^direct. Trial 2, provide information on the direct comparison between treatment Tb and Saline, denoted by θ _{Tb Saline} ^direct. Then NMA provide indirect evidence for the comparison of CHX and Tb from the treatment difference CHX and Saline and Tb and Saline as follows:

θ _{CHX Tb} ^indirect  = θ _{CHX Saline} ^direct - θ _{Tb Saline} ^direct and the variance of this association is given by the Var (θ _{CHX Tb}^indirect) = Var(θ _{CHX Saline} ^direct ) + Var (θ _{Tb Saline} ^direct ). So as to have the NMA combination for the direct and indirect comparisons, we are assuming that the trial 1 and 2 are independent, the underlying effects are consistent and any differences in the data are due to random error. The NMA now has a consequent network having its integer of total treatments, designs (a design refers to each combination of treatment), pairwise comparisons and its subsequent statistical inferences of all the included studies.

Methods

Results

Discussion

We applied NMA to an existing and robust pairwise meta-analysis to assess the utility of this novel analytic in defining a hierarchical comparison to determine the effectiveness of oral interventions in preventing VAP. [5] Our results suggest that the application of NMA to a conventional meta-analysis provides additional actionable information relative to preventing VAP by comprehensively comparing treatment options otherwise sequestered in pairwise comparisons.

These results have to be taken with caution as the assumptions are based on the results of multiple comparisons. This novel technique allows us to presume direct and indirect comparison performed in a structured statistical framework. Although the inferences are from low risk and unclear risk of bias RCTs, estimated network and ranking of treatment are thus liable to have distinctions as discussed in this NMA and previous pairwise meta-analysis. [5] A potential value of the method is its informative function relative to directing future studies and, in this case, a specific trial assessing preventive interventions for VAP in critically ill patients. The NMA is a comprehendible way of combinations which stem a possibility of consolidating a future trial from the network. Consequently, the NMA when compared to pairwise meta-analysis, weighs the logical possibilities, even within the network while maintaining the internal randomization of the individual trails.

In comparison with the published pairwise meta-analysis, the NMA showed a divergent finding with respect to the ranking probabilities from the multiple comparisons. [3–5] This is the first NMA in this regard to report on comparative effectiveness research on oral care intervention for preventing VAP. In contrast to standard of care where CHX is described as the best oral care intervention to prevent VAP, NMA demonstrated the superiority of tooth brushing or mechanical cleaning. This finding is especially significant given the recent findings associated with CHX toxicity. [16] We also determined toothbrushing when combined with a mouthwash is superior compared to a mouthwash alone; toothbrushing with PI is superior to any other mouthwash or ranking second in the first three-best interventions. This is the first time showing the superior benefit of the furacillin as a mouthwash in preventing the VAP. Furacillin belongs to the nitrofuran class and is a potent antimicrobial organic compound. It is efficient against gram-positive bacteria and gram-negative bacteria. Studies shows furacillin effective against many bacterial and fungal entities when applied topically. [17] Although there aren’t many studies on this intervention, this network warrants a possible pilot trial. The PMA showed weak evidences of the PI superior than saline in preventing VAP, and inadequate evidences of the toothbrushing preventing VAP in critically ill patients. [5] The NMA shows toothbrushing alone or toothbrushing along with PI are the best interventions according to the clinical comparative effectiveness research.

There are lack of comparative effectiveness research and vagueness with regard to OCI in preventing VAP among critically ill patients and NMA is never performed. While our results support the usefulness of NMA as a tool to optimize collective analyses of meta-analyses for comparative effectiveness research, it does have limitations. For justifying the rationality of findings and to minimalize error, NMA is designed methodically and conducted carefully. Transporting the high-quality systematic search and search results of the Hua et al study, [5] we established our own inclusion and exclusion criteria for building NMA network. We argue that this way we pragmatically compared the PMA to the NMA and reflected on its comparative effectiveness research. Observing fewer research on OCI on preventing the VAP in critically ill patients after the Hua et al study and using the Hua et al research supplemented NMA construction, which defends the judicious literature search along with assessing risk of bias and quality of evidence. But challenges of the NMA persists when comparing the studies with low and unclear-risk biases. In summary, this research accomplishes to provide comparative effectiveness of OCIs in preventing VAP in critically ill patients when combining direct and indirect evidences by having a transitivity assumption that studies are independent and underlying effects are somewhat consistent.

Conclusions

As meta-analysis is considered epitome of the evidence-based clinical medicine, NMA is an extension positioned in this framework. Given the challenges of the proof of concept of existing oral care intervention in preventing VAP, and lack of head to head robust trials of the best available treatment modalities, this approach is exceptional. We followed stern assumptions and standardization and our study cohort was based on the largest pairwise meta-analysis of oral care intervention in preventing the VAP. The transparency, reproducibility and detailed documentation of our finding can be appropriately appraised. According to the NMA outcome, toothbrushing alone or toothbrushing along with a potent antiseptic mouthwash povidone iodine was related to the highest response rate in preventing VAP in critically ill patients followed by furacillin and chlorhexidine 0.2%, respectively.

Abbreviations

Declarations

• Ethics approval and consent to participate – NA
• Consent for publication -NA
• Availability of data and material - NA
• Competing interests- No competing interests
• Funding- No funding received for this manuscript.
• Authors' contributions

Satheeshkumar PS: Study design, statistical analysis, data interpretation, manuscript drafting, revision, and critical evaluation

Sonis S: Study design, data interpretation, manuscript revision and critical evaluation.

Acknowledgements- NA

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