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 Table of Contents  
SYSTEMATIC REVIEW AND META-ANALYSIS
Year : 2017  |  Volume : 1  |  Issue : 1  |  Page : 6-23

Postpyloric feeding in critically ill patients: Updated systematic review, meta-analysis and trial sequential analysis of randomized trials


1 Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Abu Dhabi, UAE
2 Department of Medicine, McMaster University, Hamilton, Canada
3 Department of Surgery, Division of Neurosurgery, McMaster University, Hamilton, Canada
4 Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Canada
5 Department of Emergency Medicine, McMaster University, Hamilton, Canada
6 Department of Medicine; Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Canada

Date of Web Publication23-Jun-2017

Correspondence Address:
Waleed Alhazzani
Department of Medicine, Division of Critical Care, McMaster University, St. Joseph's Healthcare Hamilton, 50 Charlton Avenue, Postal Code L8N 4A6, Hamilton, Ontario
Canada
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2543-1854.208928

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  Abstract 

Background: Current guidelines recommend early enteral nutrition in the critically ill. Nutritional deficiencies in this population may result in unfavorable outcomes. However, enteral nutrition may be complicated with feeding intolerance, aspiration, pneumonia, and interruption of feeding. Objectives: We updated our systematic review and meta-analysis that compared the effect of postpyloric and gastric feeding on risk of pneumonia, duration of mechanical ventilation (MV), Intensive Care Unit (ICU) length of stay (LOS), gastrointestinal (GI) bleeding, aspiration, vomiting, and mortality. Methods: We searched MEDLINE, EMBASE, and clinical registries for data through April 2017 without language or date of publication restrictions. We included randomized controlled trials (RCTS) comparing postpyloric feeding to gastric feeding. Two reviewers independently screened titles and abstracts for eligibility and extracted data in duplicate. Reviewers used the Cochrane Collaboration tool to assess the risk of bias, and the Grading of Recommendations, Assessment, Development, and Evaluation methodology to assess the quality of the evidence. We used trial sequential analysis (TSA) as a sensitivity analysis to adjust for sequential testing. Results: We included 21 RCTs (1573 patients). Postpyloric feeding reduced the risk of nosocomial pneumonia (relative risk [RR] 0.73; 95% confidence interval [CI] 0.57, 0.95; P = 0.02; I2 = 11%; moderate quality), ventilator-associated pneumonia (RR 0.74, 95% CI 0.57, 0.96; P = 0.02; I2 = 10%, moderate quality), and duration of MV (mean difference [MD] - 2.10 days, 95% CI −3.93, −0.28; P = 0.02; I2 = 67%, low quality), compared to gastric feeding. There was no difference in mortality (RR 1.07, 95% CI 0.90, 1.27; P = 0.44; I2 = 0%, moderate quality), ICU LOS (MD - 1.01 days, 95% CI −3.32, 1.3; P = 0.39; I2 = 84%, very low quality), aspiration (RR 0.81, 95% CI 0.4, 1.60, P = 0.54; I2 = 21%, very low quality), vomiting (RR 0.97, 95% CI 0.70, 1.36, P = 0.87; I2 = 33%, very low quality), and GI bleeding (RR 0.88, 95% CI 0.56, 1.38; P = 0.56; I2 = 0%, very low quality). Sensitivity analysis using TSA mirrored those of conventional analyses. Conclusions: Moderate quality evidence showed that postpyloric feeding may reduce the risk of pneumonia. Low-quality evidence yielded that duration of MV is shorter with pyloric compared to gastric feeding, with no significant impact on other outcomes. Although the results are promising further assessment in large clinical trials is warranted.

Keywords: Critical care, enteral nutrition, gastric feeding, postpylorc feeding


How to cite this article:
Alshamsi F, Utgikar R, Almenawer S, Alquraini M, Baw B, Alhazzani W. Postpyloric feeding in critically ill patients: Updated systematic review, meta-analysis and trial sequential analysis of randomized trials. Saudi Crit Care J 2017;1:6-23

How to cite this URL:
Alshamsi F, Utgikar R, Almenawer S, Alquraini M, Baw B, Alhazzani W. Postpyloric feeding in critically ill patients: Updated systematic review, meta-analysis and trial sequential analysis of randomized trials. Saudi Crit Care J [serial online] 2017 [cited 2018 May 23];1:6-23. Available from: http://www.sccj-sa.org/text.asp?2017/1/1/6/208928


  Introduction Top


Critically ill patients are prone to nutritional deficiencies during Intensive Care Unit (ICU) stay which can lead to adverse outcomes such as prolonged mechanical ventilation (MV) and ICU stay complicated by the risk of infections and mortality.[1] As such, the American Society of Parenteral and Enteral Nutrition guidelines [2] recommend initiation of enteral nutrition within 24–48 h of ICU admission and increase to goal within 1 week which is in agreement with the 2012 Surviving Sepsis Campaign (SCC) guidelines [3] which also recommend enteral nutrition as the preferred mode of delivery. The mode of delivery in most patients is gastric feeding, however, gastrointestinal (GI) intolerance occurs in up to 50% of mechanically ventilated patients, which can increase the risk of aspiration and pneumonia.[2] Several options are recommended to enhance tolerability and reduce complications, which include the use prokinetic agents, continuous feeding, chlorhexidine mouthwash, elevation of the head of the bed, and postpyloric nutrition delivery.[2]

Our meta-analysis published in 2013 included 19 randomized controlled trials (RCT) with 1385 patients showed that postpyloric feeding probably reduces the risk of pneumonia with no effect on other clinical outcomes when compared to gastric feeding.[4] However, the quality of evidence for pneumonia outcome was low. In view of the new evidence of potentially higher quality, we updated our systematic review and meta-analysis, the results of this systematic review were used to formulate recommendations in the recent SSC guidelines.[5]


  Methods Top


Search strategy

We updated our search of MEDLINE and EMBASE from January 2013 to April 2017 without language or publication date limits. We searched clinical trials.gov, International Clinical Trials Registry Platform and International Standard Randomized Controlled Trial Number registries up to April 2017. References of relevant studies were also screened for potentially relevant studies [Appendix Table 1].[Additional file 1]

Inclusion criteria

Trials were eligible if they were (1) randomized in design, (2) comparing parallel groups of critically ill patients (3) received enteral nutrition by either postpyloric or gastric tube (we excluded trials using gastrostomy or jejunostomy tubes) and (4) reported on any of the following outcomes: pneumonia, ventilator-associated pneumonia (VAP), mortality, ICU length of stay (LOS), duration of MV, GI bleeding, aspiration, and vomiting.

Two reviewers (FA and RU), independently and in duplicate, screened titles and abstracts for eligibility and for full manuscript review. We resolved the disagreement between reviewers by consensus and consulted with a third reviewed when needed. Weighted Kappa statistics was used to measure the agreement between reviewers.[6]

Data extraction and risk of bias assessment

Two reviewers (FA and RU), independently and in duplicate, extracted data from all new studies and assessed risk of bias using the Cochrane Collaboration risk of bias tool.[7] Each of the following domains: adequate sequence generation, allocation sequence concealment, blinding for objective outcomes, incomplete outcome data, selective outcome reporting, and other bias were assessed as having low, unclear or high risk of bias. For a trial to be of low overall risk, all domains should be of low risk of bias and for overall unclear risk, at least one domain should be of unclear risk of bias but no domain of high risk of bias, whereas high overall risk of bias trials have at least one domain of high risk of bias. We contacted study authors for missing or unclear information. Disagreements were resolved by discussion and consensus, or adjudication by a third reviewer. Finally, we used the Grading of Recommendations Assessment, Development, and Evaluation method to rate the quality of the evidence (the confidence in the estimates of effects).[8]

Statistical analysis

We used Review Manager (version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014)[9] to conduct all analyses. We used the DerSimonian and Laird random-effects model to pool the weighted estimates of effect across all trials.[10] Study weights were estimated using the inverse variance method. We used pooled relative risks (RR) with 95% confidence intervals (CIs) to report dichotomous outcomes and mean difference (MD) for continuous outcomes. Finally, we assessed for statistical heterogeneity using the I2 statistic [11] with a cutoff of >50% consistent with substantial heterogeneity. We visually assessed funnel plots for publication bias for every outcome.[12] To calculate the number needed to treat (NNT), we used the method recommended by the Cochrane Collaboration [13] and used assumed control risk (ACR) of 15% for VAP.[14]

We performed two a priori defined subgroup analyses for the outcomes of pneumonia comparing duodenal versus jejunal position of postpyloric tubes and low versus high risk of bias trials.

We performed three a priori defined sensitivity analyses to examine potential heterogeneity and to test the accuracy of our findings. In the first analysis, we excluded studies that did not provide definitions for pneumonia and VAP. In the second analysis, we used odds ratio (OR) instead of RR. Finally, we excluded studies that exclusively included patients with severe pancreatitis.

We evaluated the risk of random errors in our conventional meta-analyses by trial sequential analyses (TSA).[15],[16],[17] TSA also calculate adjusted values by serologically and sequentially adding individual RCTs to analyses. We conducted TSA with the intention to maintain an overall 5% risk of a type I error and a power of 80%. To calculate the required information size, we used a 30% relative risk reduction (RRR) in the intervention effect for pneumonia and VAP outcomes, and 10% RRR for mortality outcome. For continuous outcome measures, the optimal information size (OIS) was based on the calculated value of the included trials.[18] We presented TSA details and plots only for outcomes where ≥5% of diversity-adjusted required information size has been reached.


  Results Top


Trial identification

Our updated search identified 281 new records. After excluding duplicates, 276 records remained for titles and abstracts screening. Two hundred and seventy-four were excluded as irrelevant, and 2 full-text articles [19],[20] were reviewed for eligibility and were included in the updated analysis.[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39] We identified a study through trial registry search. However, we could not obtain additional information to allow inclusion (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12605000570684). The agreement between the two reviewers was perfect (kappa = 1.0) and no adjudication was needed by the third reviewer. In total, we included 21[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39] trials with a total of 1573 patients in different analyses [Figure 1].
Figure 1: Process of identifying eligible studies: 21 were eligible and were included in the qualitative and quantitative analyses

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Characteristics of included trials

Studies included a wide variety of critically ill medical, surgical and trauma patients. Six studies used nasoduodenal (ND) tubes, eleven used naso-jejunal tubes and four did not specify the location after the pylorus. The definition of pneumonia varied between studies, we described those definitions in [Table 1]. Elevation of the head of the bed as a measure for VAP prevention was clearly stated in eight trials, but no other preventive measures were reported. Most trials allowed the use of prokinetic agents for insertion of postpyloric tubes or for feeding intolerance.
Table 1: Studies characteristics

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Risk of bias

Using the Cochrane risk of bias tool, the overall risk of bias in the studies was high in 14, unclear in 2 and low in 5. Details of the risk of bias assessment are presented in [Appendix Figure 1] [Additional file 2].

Visual inspection of funnel plot for the outcome of pneumonia did not show evidence of publication bias.

Outcomes

Nosocomial pneumonia

Fourteen trials [19],[20],[23],[24],[25],[29],[30],[31],[32],[33],[34],[35],[38],[39] enrolling 1179 patients reported on pneumonia [Figure 2]. The use of postpyloric feeding was associated with significantly lower risk of pneumonia compared with gastric feeding (RR 0.73, 95% CI 0.57, 0.95; P = 0.02; I2 = 11%, moderate quality) which translates to an absolute risk reduction in pneumonia of 2.5% (95% CI 0.6%, 4.1%) and a NNT of 25 for an ACR of 15%.
Figure 2: Forest plot of postpyloric feeding versus gastric feeding on pneumonia outcome

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Ventilator associated pneumonia

Nine trials [20],[24],[29],[30],[31],[32],[35],[38],[39] enrolling 950 patients reported on VAP [Figure 3]. The use of postpyloric feeding was associated with lower risk of VAP compared to gastric feeding (RR 0.74, 95% CI 0.57, 0.96; P = 0.02; I2 = 10%, moderate quality). The NNT is 26 for an ACR of 15%.
Figure 3: Forest plot of postpyloric feeding versus gastric feeding on ventilator associated pneumonia outcome

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Mortality

Sixteen trials [20],[21],[24],[25],[26],[27],[29],[30],[31],[32],[33],[34],[35],[37],[38],[39] enrolling 1,347 patients reported on morality [Figure 4]. No significant difference in mortality between groups (RR 1.07, 95% CI 0.9, 1.27; P = 0.44; I2 = 0%, moderate quality).
Figure 4: Forest plot of postpyloric feeding versus gastric feeding on mortality outcome

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Intensive Care Unit length of stay

Nine trials [19],[23],[24],[29],[30],[31],[34],[35],[39] enrolling 832 patients reported on ICU LOS [Figure 5]. ICU LOS was similar in both groups (MD - 1.01 days, 95% CI -3.32, 1.3; P = 0.39; I2 = 84%, very low quality).
Figure 5: Forest plot of postpyloric feeding versus gastric feeding on Intensive Care Unit length of stay outcome

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Duration of mechanical ventilation

Four trials [19],[29],[34],[39] enrolling 333 patients reported the duration of MV [Figure 6]. The use of postpyloric feeding was associated with shorter duration of MV (MD - 2.10 days, 95% CI −3.93, −0.28; P = 0.02; I2 = 67%, very low quality).
Figure 6: Forest plot of postpyloric feeding versus gastric feeding on duration of mechanical ventilation outcome

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Gastrointestinal bleeding

Seven trials [22],[23],[24],[29],[30],[34] enrolling 616 patients reported on GIB [Figure 7]. The risk of GIB was similar in both groups (RR 0.88, 95% CI 0.56, 1.38; P = 0.56; I2 = 0%, low quality).
Figure 7: Forest plot of postpyloric feeding versus gastric feeding on gastrointestinal bleeding outcome

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Aspiration

Seven trials [19],[24],[27],[28],[31],[36],[39] enrolling 545 patients reported on aspiration [Figure 8]. The risk of aspiration was similar in both groups (RR 0.81, 95% CI 0.4, 1.60, P = 0.54; I2 = 21%, very low quality).
Figure 8: Forest plot of postpyloric feeding versus gastric feeding on aspiration outcome

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Vomiting

Seven trials [20],[23],[28],[29],[32],[34],[35] enrolling 668 patients reported on vomiting [Figure 9]. The risk of vomiting was similar in both groups (RR 0.97, 95% CI 0.70, 1.36, P = 0.87; I2 = 33%, low quality).
Figure 9: Forest plot of postpyloric feeding versus gastric feeding on vomiting outcome

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Nutritional requirements

Reporting of nutritional outcomes varied significantly between studies. Therefore, we summarized the results of each trial in [Table 3], as meta-analysis was not feasible. Mean daily caloric intake was significantly higher in the postpyloric feeding group in four trials (n = 307) and similar to gastric feeding in three trials (n = 185). Four trials (n = 385), with different outcome definitions, reported on time to reach target caloric intake which was significantly longer in small bowel feeding group.
Table 3: Nutritional outcomes summary

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Subgroup analyses

We performed a priori subgroup analyses for outcomes of pneumonia and VAP based on feeding tube location (jejunal vs. duodenal) and risk of bias (low vs. high or unclear) which revealed no difference between subgroups [Appendix Figure 2] [Additional file 3],[Appendix Figure 3] [Additional file 4], [Appendix Figure 4] [Additional file 5],[Appendix Figure 5] [Additional file 6].

Sensitivity analyses

Although our analysis did not show any substantial heterogeneity, we performed three sensitivity analyses for the primary outcome. First analysis excluded five trials (n = 347)[19],[25],[29],[33],[35] that did not provide a definition for pneumonia, the results remained robust (RR 0.73, 95% CI 0.56, 0.95; P = 0.02, I2 = 0%) [Appendix Figure 6] [Additional file 7]. Using OR also did not significantly change the results (OR 0.64, 95% CI 0.44, 0.95; P = 0.03; I2 = 22%). Finally, excluding a trial (n = 30)[33] that exclusively included pancreatitis patients and reported on pneumonia, the results did not significantly change (RR 0.73, 95% CI 0.56, 0.94; P = 0.02; I2 = 12%) [Appendix Figure 7] [Additional file 8].

Trial sequential analysis

For nosocomial pneumonia and VAP, TSA showed that OIS was not reached (Appendix Figure 8] [Additional file 9], [Appendix Figure 9] [Additional file 10]). The TSA adjusted RR was 0.73 (95% CI 0.47, 1.14) and 0.74 (95% CI 0.42, 1.29) for pneumonia and VAP; respectively. None of the other outcomes reached OIS. TSA adjusted estimates are presented in [Table 4] and [Appendix Figure 10] [Additional file 11], [Appendix Figure 11] [Additional file 12], [Appedndix Figure 12] [Additional file 13], [Appendix Figure 13] [Additional file 14], [Appendix Figure 14] [Additional file 15], [Appendix Figure 15] [Additional file 16].


  Discussion Top


In this updated systematic review, we evaluated the impact of postpyloric feeding, compared to gastric feeding, on patient important outcomes. Overall, low to moderate quality evidence demonstrated that postpyloric feeding strategy reduced pneumonia risk (RR 0.73, 95% CI 0.57, 0.95, P = 0.02, I2 = 12%) and duration of MV (MD - 2.10 days, 95% CI −3.93, −0.28; P = 0.02; I2 = 67%), with no effect on other outcomes. Overall, low to moderate quality evidence demonstrated that post pyloric feeding strategy reduced pneumonia risk (RR 0.73, 95% CI 0.57, 0.95, P = 0.02, I2 = 12%) and duration of mechanical ventilation (MD -2.10 days, 95% CI -3.93, -0.28; P = 0.02; I2=67%), with no effect on other outcomes [Table 2]. Our results are consistent with the results of prior meta-analyses.[4] While one of the presumptive mechanisms for developing pneumonia with gastric feeding is the aspiration of gastric content, low-quality evidence from RCTs did not demonstrate reduction of aspiration risk. This could be explained by the difficulty in detecting micro-aspiration events and relying only on clinically evident aspiration, and the small number of trials (7 RCTs) reporting this outcome; which renders the quality of evidence as low at best. Furthermore, indirect RCT evidence failed to show an association between VAP and gastric residual volume (GRV) measurement, as a result, recent guidelines issued a weak recommendation against the routine measurement of GRVs, undermining the concern of aspiration and pneumonia.[5],[40]
Table 2: Evidence profile

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The lack of mortality benefit despite apparent reduction in pneumonia risk is not surprising, similarly, other VAP prevention strategies did not reduce mortality despite a significant reduction in pneumonia.[41],[42] Other factors, such as the use of parenteral nutrition to supplement caloric intake during the delay postpyloric feeding may have attenuated any impact on mortality that decreased risk pneumonia may have had, for example through the increased risk of infection associated with TPN. Inconsistency in reporting nutritional outcomes in eligible trials precluded us from performing a meta-analysis for nutritional outcomes.

Postpyloric feeding tube insertion appears to be generally safe. However, this was not included as an outcome in this analysis and as such definite conclusions cannot be drawn. There was, however, no significant difference in rates of GI bleeding between postpyloric and NG tube groups. Small bowel tubes are associated with a higher rate of failure of insertion than traditional NG tubes. As such, this may affect the time required to reach the target rate for feeds and may diminish the benefits of early feeding.

Our meta-analysis has several strengths. We included more studies than any previously published meta-analyses on this topic (21 trials with 1573 patients) which improved the precision of the results. Our search strategy was broad and did not apply publication date or language restrictions. We also sought unpublished data from authors. We conducted all a priori planned subgroup and sensitivity analyses to examine the robustness of our findings. Finally, we adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guidelines.[43] There are some limitations worth mentioning; first, we were not able to quantify the impact of postpyloric feeding on the nutritional requirement, this is caused by the inconsistency between studies in describing and reporting this outcome, which limited our ability to conduct a meta-analysis, therefore, we qualitatively described these outcomes in [Table 3]. Second, we were not able to reliably assess the feasibility issues and cost associated with postpyloric tube insertion. This could be important when translating evidence into a clinical decision.





This systematic review and meta-analysis affirm that compared to gastric feeding, postpyloric feeding probably reduces pneumonia risk. In addition, our study reveals that postpyloric feeding reduces the duration of MV, with uncertain impact on other important clinical outcomes. The quality of evidence ranged between very low to moderate. Therefore, the potential benefit of postpyloric feeding should be weighed against the feasibility of tube insertion and cost. Future, large RCTs are still warranted to confirm these observations and to more reliably determine the effect on other outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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