Variance between studies in a meta-analysis will exist. This heterogeneity may be of clinical, methodological or statistical origin. The last of these is quantified by the I(2) -statistic. We investigated, using simulated studies, the accuracy of I(2) in the assessment of heterogeneity and the effects of heterogeneity on the predictive value of meta-analyses. The relevance of quantifying I(2) was determined according to the likely presence of heterogeneity between studies (low, high, or unknown) and the calculated I(2) (low or high). The findings were illustrated by published meta-analyses of selective digestive decontamination and weaning protocols. As expected, I(2) increases and the likelihood of drawing correct inferences from a meta-analysis decreases with increasing heterogeneity. With low levels of heterogeneity, I(2) does not appear to be predictive of the accuracy of the meta-analysis result. With high levels of heterogeneity, even meta-analyses with low I(2) -values have low predictive values. Most commonly, the level of heterogeneity in a meta-analysis will be unknown. In these scenarios, I(2) determination may help to identify estimates with low predictive values (high I(2) ). In this situation, the results of a meta-analysis will be unreliable. With low I(2) -values and unknown levels of heterogeneity, predictive values of pooled estimates may range extensively, and findings should be interpreted with caution. In conclusion, quantifying statistical heterogeneity through I(2) -statistics is only helpful when the amount of clinical heterogeneity is unknown and I(2) is high. Objective methods to quantify the levels of clinical and methodological heterogeneity are urgently needed to allow reliable determination of the accuracy of meta-analyses.

Risk factors for the development of ventilator-associated pneumonia (VAP) and colonization of the respiratory tract and stomach with enteric gram-negative bacteria (EGB) and Pseudomonadaceae were determined in 141 ventilated patients using univariate analysis and the Cox proportional hazards model. VAP was caused by EGB in 14 patients (10%), and by Pseudomonadaceae in 19 patients (13%). The duration of ventilation was a significant risk factor for VAP caused by EGB and Pseudomonadaceae, and for acquired colonization in oropharynx, stomach, and trachea with these species. Of 20 other variables, oropharyngeal colonization with EGB on admission (hazard ratio [HR] = 4.5) and an infection on admission (HR = 2.7) were selected as risk factors for VAP caused by EGB. Acquired colonization with Pseudomonadaceae in oropharynx (HR = 5.0) was the most important risk factor for VAP caused by these species. Gastric colonization with EGB or Pseudomonadaceae were no risk factors for VAP. For acquired oropharyngeal colonization with EGB only the duration of ventilation was a risk factor, whereas preceding colonization of the trachea with Pseudomonodaceae and duration of ventilation were risk factors for acquired oropharyngeal colonization with these species. In the Cox model, only the duration of ventilation was significantly related to acquired gastric colonization with EGB. Preceding colonization of the orophayrnx and of the trachea with Pseudomonadaceae were risk factors for acquired colonization with these species in the stomach. Twelve patients with VAP (46%) and 38 without VAP (33%) died (p = 0.21). In conclusion, duration of ventilation and colonization of the upper respiratory tract are the most important risk factors for VAP caused by EGB or Pseudomonadaceae.

Continuous enteral feeding (CEF) has been associated with decreased gastric acidity, thereby stimulating gastric colonization and ventilator-associated pneumonia (VAP). Intermittent enteral feeding (IEF) could induce a temporary increase in gastric acidity and decrease the risk of VAP. We studied the influence of IEF (18 h/d) and CEF (24 h/d) on gastric and oropharyngeal colonization. Sixty patients were randomized to receive either IEF or CEF, and continuous intragastric pH monitoring was performed in 50 patients. Median intragastric pH levels were similar before enteral feeding was instituted (pH 2.5 for CEF and pH 2.4 for IEF), and median pH values increased slightly after institution of nutrition (NS). In patients receiving IEF, median pH decreased from 3.5 to 2.2 (p = 0.0002) when enteral feeding was discontinued. However, despite this, 80% of the patients in both study groups were colonized in the stomach after 7 d in study. In addition, colonization rates of the oropharynx and trachea, the incidence of VAP, and mortality were similar in both study groups. IEF was less well tolerated than CEF. We conclude that almost all patients receiving enteral feeding are colonized in the stomach with gram-negative bacteria. IEF resulted in a slight decrease in intragastric pH without influencing rates of colonization and infection of the respiratory tract.

Ventilator-associated pneumonia (VAP) is the most frequent occurring infection among mechanically ventilated patients. The clinical presentation of VAP ranges from relatively benign to a severe illness with septic shock. The influence of VAP on patient outcome has not been elucidated and its effects on the inflammatory response of the host are unknown. In a case-control study, the systemic inflammatory response was investigated in patients developing VAP as compared with control patients matched on duration of mechanical ventilation and underlying diseases. Patients developing VAP (n = 42) were matched to a single control (without VAP), who was matched on seven variables. VAP was diagnosed with bronchoscopic techniques. The inflammatory response, reflected by circulating levels of interleukin-6 (IL-6) and interleukin-8 (IL-8), was determined on the day of diagnosis (or day of matching for controls), 4 and 2 d before diagnosis, and 2 d after diagnosis. The development of VAP was not associated with an increase in circulating levels of IL-6 or IL-8. Among patients in which VAP was associated with a clinical presentation of severe sepsis or septic shock (n = 10), IL-6 and IL-8 levels increased and were higher than in the corresponding controls. Moreover, 60% of cases with severe sepsis or septic shock died as compared with 20% of their matched controls (p = 0.06). Mortality rates were similar in patients with uncomplicated VAP and their matched controls (25% and 34%, respectively). High circulating levels of IL-6 and IL-8 were associated with higher mortality rates. The clinical picture of VAP can be subdivided into different types, ranging from uncomplicated to an infection associated with severe sepsis or septic shock, elevated circulating levels of IL-6 and IL-8, and an increased mortality rate.

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