Aconsensus conference recommended performing tracheotomy after 3 weeks of endotracheal intubation in patients with prolonged mechanical ventilation.1 In reality, there is a big variation of timing and methods of tracheotomy in different countries and regions.2 Tracheostomy offers the potential advantages for patients such as improved comfort, ability to communication, opportunity for oral feeding, and easier and safer nursing care. Less need for sedation and lower airway resistance after tracheostomy may facilitate the weaning process and shorten intensive care unit (ICU) and hospital stay. By preventing microaspiration of secretions, tracheostomy may also reduce ventilator associated pneumonia (VAP).3 Rumbak et al4 showed that tracheotomy within 2 days of hospital admission reduced the mortality, incidence of pneumonia, and length of ICU stay compared with tracheotomy performed after 14 to 16 days of endotracheal intubation. Blot et al5 showed that mortality, duration of mechanical ventilation (MV) and ICU stay, and incidence of infections did not differ between patients randomized to receive a tracheotomy within 4 days following onset of mechanical ventilation and those randomized to maintain endotracheal intubation for at least 14 days. In addition, in comparison to the surgical tracheostomy (ST) technique, percutaneous dilational tracheotomy (PDT), which have been widely applied in critically ill patients, had shorter procedure time and may have a lower complication and mortality rate.6,7 The current study investigated the hypothesis that early PDT performed at day 3 of endotracheal intubation compared with late PDT performed at day 15 of endotracheal intubation would reduce duration of MV, sedative use and ICU stay, incidence of VAP and increase successful weaning and ICU discharge rate.
Under a protocol approved by the Ethics Committee of Chaoyang Hospital, Beijing, China, all patients older than 18 years treated with MV via endotracheal intubation between July 1, 2008 and June 30, 2011 in a 19-bed surgical ICU of a university affiliated hospital were screened for this prospective randomized trial. Patients were excluded if they had anatomical neck deformity, thyromegaly or cervical tumors, hematological malignancy, or previous tracheostomy; were pregnant; or weaned or died during 48 hours after MV onset. The remaining patients continued to be screened at day 3 of MV. They were included in the study if they had been mechanically ventilated for acute respiratory failure with PaO2/FiO2 (fraction of inspired oxygen) less than or equal to 200 mmHg; had an acute physiology and chronic health evaluation score II (APACHE II)8 more than 15; had a sequential organ failure assessment (SOFA)9 score equal to or greater than 5; did not have a pulmonary infection estimated by a modified clinical pulmonary infection score (CPIS)10 more than 6; and were estimated to require MV more than 14 days by the two attending physicians. Patients were excluded if they had significant coagulopathy or were moribund (Figure 1).
The patients who had been included were randomly assigned to the early PDT group or the late PDT group. The patients in the early PDT group were tracheostomized with PDT on day 3 of MV and ventilated continuously after that. The patients in the late PDT group were continuously ventilated via endotracheal intubation and tracheostomized with PDT on day 15 of MV if they still needed MV (Figure 1). PDT was performed by experienced physicians under bronchoscopic guidance using Griggs et al’ method.11 The random assignments were generated by computer and then concealed in sealed envelopes. Patient assignment was known only by the study investigators. Sedatives were given on an open-label basis. Weaning from mechanical ventilation and use of sedatives and analgesics were guided by a standard protocol. All patients in both groups were sedated by intravenous propofol infusion. When analgesia was needed, an infusion of fentanyl was given simultaneously. Propofol was initially infused at 0.3 mg·kg-1·h-1 and the dosage was increased every 2 minutes with increment of 0.1 to 0.2 mg·kg-1·h-1 until adequate sedation was achieved. The sedative goal was to achieve a score of 3 to 4 on the Ramsay sedation scale.12,13 Fentanyl was continuously infused at 0.7 to 10 μg·kg-1·h-1 until pain was controlled. All patients were ventilated using the volume assist-control mode of ventilation with a tidal volume of 6 to 8 ml per kilogram of predicted body weight. The goal was a saturation of peripheral blood oxygen (SpO2) as measured by means of pulse oximetry of 88% to 95% or a PaO2 of 55 to 80 mmHg. To achieve this goal, FiO2 and the positive end-expiratory pressure were adjusted according to the protocol described in the prospective, randomized, multi-center trial of 12 ml/kg tidal volume positive pressure ventilation for treatment of acute lung injury and acute respiratory distress syndrome.14 Evidence-based guidelines for weaning and discontinuing ventilatory support15 were used for the weaning strategies.
The primary outcome was ventilator-free days at day 28 after randomization. The secondary outcomes were sedation-free and ICU-free days, successful weaning and ICU discharge rate, incidence of VAP at day 28 after randomization. The cumulative 60-day incidence of death after randomization was also followed up. This study was performed in a single center which all patients were managed according to same management procedures, therefore, the effects of management heterogeneity on study results were limited.
Hypoalbuminemia was defined as serum albumin less than or equivalent to 25 g/L. The presence of VAP was defined using the modified clinical pulmonary infection score (CPIS).10 A CPIS greater than 6 was considered to indicate the presence of VAP.10 The CPIS score was calculated at the randomization day, and every 72 hours since until day 28 after randomization. The APACHE II8 score and SOFA9 score were calculated according to their evaluation criteria at ICU admission and randomization day. A sedative day was defined as a day from 6 a.m. to next 6 a.m. with a cumulative sedative duration more than 12 hours. The sedation-free days equaled to 28 days minus cumulative sedation days within 28 days after randomization. Similarly, the ICU-free days, ventilator-free days were calculated. ICU discharge was defined as a patient's discharge from ICU within 28 days after randomization. The cumulative 60-day incidence of death was calculated from randomized day to day 60 after randomization.
The following complications associated with PDT during the 28-day study period after randomization were recorded: (1) intraoperative: minor bleeding (bleeding less than 100 ml), significant bleeding (any bleeding event that required blood transfusions), difficult tracheostomy tube placement (requiring at least 2 attempts for insertion during primary placement procedure), hypoxemia (SpO2 <90% for more than 90 seconds), arrhythmia, and cardiac arrest; and (2) postoperative: stoma inflammation, stoma infection, minor bleeding, significant bleeding, pneumothorax, subcutaneous emphysema, tracheoesophageal fistula, or cannula displacement or need for cannula replacement.16
Characteristics of study population and clinical variables according to the early PDT and late PDT groups at ICU admission and randomized day were shown in Table 1. Continuous variables were presented as mean ± standard deviation (SD) or median (interquartile range, IQR). Categorical variables were presented as number and percent. The continuous variables of normal distribution and skewed distribution were analyzed by the Fisher exact test and the Wilcoxon signed rank test, respectively. A χ2 test was used to analyze categorical variables. The patients' death time was censored on day 60 after randomization. The cumulative 60-day incidence of death was calculated according to the Kaplan-Meier method. The Log-rank test was used to compare the cumulative 60-day incidence of death between the early PDT group and the late PDT group. All analyses were performed using the SPSS 11.5 package (SPSS for Windows, version 11.5, SPSS Inc, Chicago, USA). P value less than 0.05 was considered as statistically significant.
Four hundred and ninety-five patients were screened on day 3 of MV, 119 patients meeting the inclusion criteria were randomized into the early PDT group (n=58) and the late PDT group (n=61) (Figure 1). Baseline characteristics at admission and before randomization did not significantly differ in the two groups (Table 1). All the 58 patients in the early PDT group received PDT. Of the 61 patients randomized into the late PDT group, 5 died and another 5 weaned within 14 days after MV onset. The remaining 51 patients received PDT on day 15 of MV. Complications of PDT are summarized in Table 2. In the 109 patients received PDT, 27 (14 in the early PDT group and 13 in the late PDT group) experienced complications associated with PDT (Table 2). The incidence of total complications was not significantly different between the two groups (P=0.710) (Table 2). No death related to PDT occurred in any group.
The ventilator-free, sedation-free and ICU-free days were (9.57±5.64) days, (20.84±2.35) days and 8.0 (IQR: 5.0-12.0) days respectively in the early PDT group and (7.38±6.17) days, (17.05±2.30) days and 3.0 (IQR: 0.0-12.0) days respectively in the late PDT group. The ventilator-free, sedation-free and ICU-free days were significantly greater in the early PDT group than in the late PDT group (P=0.046, P=0.048 and P <0.001, respectively) (Table 3).
The successful weaning and ICU discharge rate were significantly higher in early PDT group than in late PDT group (74.1% vs 55.7%, P=0.036; and 67.2% vs 47.5%, P =0.03 respectively) (Table 3). VAP was observed in 17 patients in the early PDT group (29.3%; 95% confidence interval (CI): 17.6%-41%) and 30 patients in the late PDT group (49.2%; 95% CI: 36.7%-61.7%) (P=0.027) (Table 3). The 28-day mortality was 13.8% (95% CI: 4.9%-22.7%) in the early PDT group and 9.8% (95% CI: 2.3%-17.3%) in the late PDT group (P=0.551) (Table 3).
Figure 2 shows the Kaplan-Meier curves for cumulative 60-day incidence of death after randomization according to the early PDT and late PDT groups. There was no significant difference in the cumulative 60-day incidence of death between the two groups (P=0.949).
Prolonged endotracheal intubation is known to be associated with airway tissue trauma, infection, and patient discomfort and usually require high doses of sedation.17,18 Less sedation and analgesia requirements19 and reduced airway resistance are thought to facilitate the weaning process.20 Furthermore, VAP may also be reduced by substituting a endotracheal intubation by tracheostomy.18
The present study showed that the early PDT given on day 3 of endotracheal intubation compared with the late PDT given on day 15 increased ventilator-free days, sedation-free and ICU-free days, and successful weaning and ICU discharge rate and reduced incidence of VAP. The replacement of ST by PDT is one possible reason for achieving the aforementioned benefits observed in the present study. Earlier studies had shown no difference in acute complications between PDT and ST.21 Delaney et al7 recently conducted a meta-analysis including 17 randomized controlled trials with a total of 1212 study participants. They demonstrated reduced incidence of wound infection and overall risk of death using PDT. While PDT and ST appeared to have similar overall incidences of clinically relevant bleeding, major periprocedural and long-term complications, subgroup analysis revealed that PDT was superior to ST when ST was performed in operating room. PDT was at least as safe as ST in terms of periprocedural complications.7 In the present study, the overall incidence of complications was 24.1% in the early PDT group and 25.5% in the late PDT group. No serious complications such as uncontrollable bleeding, tracheoesophageal fistula, refractory arrhythmia, or cardiac arrest occurred. The lack of serious complications or death related to PDT indicated that PDT performed under bronchoscopic guidance is safe and feasible to use in ICU.
The timing for PDT (on day 3 of MV in the early PDT group) is as another possible reason for the variety of benefits in the present study. How earlier tracheostomy should be performed in patients requiring prolonged MV is still being debated. The study by Rumbak et al4 showed that patients with tracheotomy performed within 2 days of admission had reduced 30-day mortality rate, pneumonia incidence, and ICU stay length compared with patients with tracheostomy performed at day 14 to 16 of admission. A recent study performed by Terragni et al22 showed early tracheotomy (6 to 8 days after endotracheal intubation) compared with late tracheotomy (13 to 15 days after endotracheal intubation) did not result in statistically significant improvement in incidence of VAP, but reduced duration of MV and ICU stay significantly in adult ICU patients. It is obvious that the benefits to the patients in the study by Rumbak et al4 were superior to that in the study by Terragni et al.22 This suggests that the earlier the tracheostomy is performed, the greater patient's benefits are.
Theoretically, MV patients require less sedation and analgesia after endotracheal intubation being replaced by tracheosotomy.20 In addition, the reduced airway resistance may facilitate the weaning process which in turn can decrease the incidence of VAP.18,21 Therefore, it is logic to believe that earlier tracheostomy may be more beneficial for patients requiring prolonged MV as long as the complications of tracheostomy are controllable.
Whether the early tracheostomy can decrease mortality is still unclear in the patients requiring prolonged MV. Rumbak et al4 found a 50% reduction in mortality rate after early tracheostomy compared with delayed tracheostomy in medical ICU. More patients died of VAP in the delayed tracheostomy group than in the early tracheostomy group. In a retrospective study,23 the overall ICU, hospital and 1-year survival rates were lower in patients receiving early tracheostomy compared with patients receiving MV for more than 24 hours without a tracheostomy. A recent meta-analysis24 including 7 randomized controlled trials studies found the timing of tracheostomy was not correlated with a markedly reduced duration of MV or sedation, shorter stay in ICU or hospital. In contrast, another recent meta-analysis3 found lower overall mortality with early tracheostomy performed within 5 days after MV onset. In the present study, the early PDT compared with late PDT did not reduce the cumulative 60-day incidence of death after randomization although MV duration and incidence of VAP was decreased in the early PDT group. Effects of early tracheostomy on mortality varied in different studies.3,24 We think the differences in inclusion criteria, definition of early tracheostomy, methods of tracheostomy, underlying diseases, severity of illness, comorbidity, and study quality might have affected the results of this studies.2,3,25,26 The decreased incidence of VAP and MV duration were not sufficient to improve the cumulative 60-day incidence of death in the early PDT group in our study. In contrast with previous studies on early vs. late tracheostomy,21,24 all the PDTs in our present study were performed with Griggs et al’ method11 under bronchoscopic guidance which have limited the effects of inconsistent tracheostomy methods on the results of this study.
This study has several limitations. First, 10 out of the 61 patients randomized to the late PDT group designed to receive PDT on day 15 after MV onset did not have PDT due to death or weaning. This indicates that our inclusion criteria could not accurately predict which patients required prolonged ventilation more than 14 days, therefore necessary tools are required to predict duration of MV in the future.3,27 All the 61 patients in the late PDT group were included in the final statistical analysis. Second, few of patients requiring prolonged MV were not enrolled to the present study due to their contraindication for PDT. Finally, the bed to nurse ratio in our ICU was 1:2.5 during the period of this study. Insufficient nurses might have increased incidence of VAP,28 and might in turn have increased duration of MV, length of ICU stay, and mortality in the studied cohort.
In conclusion, early PDT resulted in increased ventilator-free, sedation-free and ICU-free days, increased successful weaning and ICU discharge rate, reduced incidence of VAP, but it did not reduce the cumulative 60-day incidence of death in the patients anticipated requiring prolonged mechanical ventilation. Prospective, randomized controlled trials are needed to further confirm these conclusions.
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