High Tidal Volumes in Mechanically Ventilated Patients Increase Organ Dysfunction after Cardiac Surgery

• High tidal volume in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) lead to ventilator-induced lung injury and increased mortality, but optimal tidal volume for mechanically ventilated patient without ALI/ARDS remains controversial.

• After cardiac surgery, tidal volume above 10 ml/kg predicted body weight is a significant risk factor for organ failure, multiple organ failure, and prolonged stay in the intensive care unit. Women and obese patients are particularly exposed to high tidal volume.

HIGH tidal volumes in mechanically ventilated patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) lead to baro- and bio-trauma1,2and increased mortality.3,4Few studies have investigated patients without ALI/ARDS, but several suggest that high tidal volumes may also be deleterious for them.5,–,9It has recently been shown that ventilation with high tidal volumes is a risk factor for acquired ALI in a medical population.5,6,10Some authors plead for the generalization of a protective ventilatory strategy to many mechanically ventilated patients, especially in those at risk of developing lung injury.11In the case of cardiac surgery, most patients have normal lungs before surgery. Although mechanical ventilation is usually delivered for several hours, respiratory mechanics are transiently affected within the first few hours of surgery.12In addition, systemic inflammation because of different causes (cardiopulmonary bypass, multiple transfusions) is frequent after cardiac surgery and may be further aggravated by injurious ventilation, even if it is only delivered for a few hours.13However, low tidal volumes are not recommended in surgical settings14,15because a reduction in tidal volume is associated with hypoxemia, probably by promoting atelectasis.16,17The aim of this study was to evaluate the clinical impact of high tidal volumes after cardiac surgery. Our hypothesis was that use of high tidal volumes delivered immediately after cardiac surgery increases organ failure.

We examined prospectively recorded data of adult patients who underwent coronary-artery bypass grafting, cardiac-valve surgery, or a combination of procedures with sternotomy and cardiopulmonary bypass at the Quebec Heart and Lung Institute from January 30, 2004, to March 30, 2006. We excluded patients who had received heart transplants, mechanical heart support, or descending aorta surgery, as well as patients who had received other infrequent surgical procedures such as minimally invasive valve surgery. Standard practices for cardiac surgery and anesthesiology during the period under study did not vary. The lungs were not ventilated during cardiopulmonary bypass. After cardiopulmonary bypass, connection to the ventilator was followed by recruitment maneuvers. The ventilator mode was synchronized intermittent mandatory ventilation with respiratory rate usually set at 10 breaths/min, the positive end-expiratory pressure (PEEP) at 5 cm H²O, and fraction of inspired oxygen (FIO2) ranged from 70 to 100%, as recommended in anesthesiology textbooks.14,15Patients were managed using fast-track procedures, with early termination of sedation (propofol) and minimal analgesic (fentanyl) after rewarming at 36°C.18Patients were extubated as soon as possible when their hemodynamic, ventilatory, and neurologic states were deemed to be stable by the attending physician, and in the absence of severe bleeding. The ventilatory protocol for the postoperative period was managed by respiratory therapists for the FIO2 weaning and for the switch to pressure support ventilation. Modifications of other ventilatory parameters (mainly respiratory rate and tidal volume) were managed by anesthesiologists or intensive care physicians based on arterial blood gas results.

We used the cardiac surgery database of our institution. Data are prospectively collected by clinical coordinators (surgeons, anesthesiologists, perfusionists, and research nurses) concurrently with patient care and are entered into the database by two trained full-time data-management personnel. We used the initial tidal volume on arrival at the intensive care unit (ICU) for all the analyses; 84% of patients were ventilated with this initial tidal volume during the entire time spent on synchronized intermittent mandatory ventilation. The remaining 16% had a tidal volume reduction after arterial blood gases analysis, but they were exposed to the tidal volume used for analysis for a minimum of 63 ± 26 min after the surgery. The patients were measured with a height gauge before surgery. Predicted body weight was calculated using a reference formula.3The cardiac surgery database was approved by the ethics committee of our institution (Comité d'éthique de la recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec, Canada) for research use without the need for patient consent.

We defined three groups of patients based on initial tidal volume on arrival to the ICU: (1) low tidal volumes (less than 10 ml/kg of predicted body weight), (2) traditional tidal volumes (10–12 ml/kg of predicted body weight), and (3) high tidal volumes (more than 12 ml/kg of predicted body weight). The choice of these tidal volume ranges was based on the literature3,11,14,15and on a model describing the impact of tidal volume on organ failure (fig. 1).

Our primary endpoint was organ dysfunction: prolonged mechanical ventilation (more than 24 h), prolonged hemodynamic instability (use of inotropes or vasopressors for more than 48 h after surgery), or renal failure (increase in creatinine levels more than 50 μM after surgery compared with baseline values). These complications are defined in the adult cardiac surgery database of the Society of Thoracic Surgeons.#The choice of these organ failures has several advantages: their definitions rely on objective criteria and they are associated with poor long-term outcome (fig. 2). We have considered the presence of one organ failure as well as multiple organ failure (at least two).

Our secondary endpoints were duration of mechanical ventilation, ICU and hospital stay, and ICU, hospital, and long-term mortality. We obtained the follow-up survival status from the Quebec Registry of the Social Security Death Index. The closing date for the data were December 31, 2009.

Continuous variables are expressed as means (SD) and categorical variables as percentages. Group comparisons were analyzed using one-way ANOVA for continuous variables and the chi-square test for categorical variables. Post hoc  comparisons were performed using the Tukey post hoc  test. A logistic regression analysis was performed to identify variables independently associated with organ failure definitions. Continuous variables were checked for the assumption of linearity in the logit using quartiles of the distribution and fractional polynomials before building the model in order to obtain the correct relationships. The graphic representations suggested linear relationships with the logit for all continuous variables. Variables from univariate logistic regressions with P < 0.20 were candidates for the multivariate regression model building. The variables were selected using two statistical approaches. First, stepwise and backward selections of variables were used in the multivariate regression model. Both approaches gave similar results. An alternative procedure to select variables was to use the best subset selection containing two to nine variables. Akaike and Sawa Bayesian information criteria were computed to validate the model selected. Conclusions were similar for both methods. To assess goodness-of-fit (calibration) for the model, a Hosmer-Lemeshow decile of risk test, Osius-Rojek normal approximation of the Pearson chi-square statistic distribution, and Stukel two degree-of-freedom test were performed. In order to appreciate the appropriate functional form between organ failure definitions and tidal volume/predicted body weight, a generalized additive model was built using the binary distribution. Smoothing was performed by spline fitting (df = 4). A linear regression analysis was performed to identify variables independently associated with length of ICU stay. The dependant variable was log-transformed to respect the linearity assumption with the continuous independent variables. The selection variables were performed using the stepwise and backward selections and the use of the best subset selection. Akaike and Sawa Bayesian information criteria were computed to validate the model selected, and conclusions were similar for both statistical approaches. As the statistics may vary from sample to sample and inference about the population must take into account these variations, we used the bootstrap technique to approximate the sampling distribution; 1,000 samples with replacement were performed. Kaplan–Meier analysis was used to examine differences in unadjusted survival without or with organ failure, with the log-rank tests used for comparison. Two-tailed values of P < 0.05 were considered significant. The univariate normality assumptions were verified using the Shapiro-Wilk test. Brown and Forsythe's variation of Levene's test statistic was used to verify the homogeneity of variances. All analyses were conducted using the SAS statistical package, version 9.2 (SAS Institute Inc., Cary, NC).

During the 26-month study period (January 2004–March 2006), 4,203 patients underwent cardiac surgery, and 3,434 patients were included in the analysis (fig. 3).

Among the included patients, coronary artery bypass graft alone was performed in 453 (62.6%), 1,057 (67.5%), and 741 patients (64.8%) respectively for low, traditional, and high tidal volumes, respectively. Valve repair alone were performed in 77 (10.1%), 133 (8.5%), and 140 patients (12.2%) for low, traditional, and high tidal volumes, respectively. Finally, combined surgery (coronary artery bypass graft surgery + valves or more than one valve repair) were performed in 170 (23.5%), 355 (22.6%), and 239 patients (20.9%) for low, traditional, and high tidal volumes, respectively.

Mean tidal volume/actual weight and mean tidal volume/predicted body weight were 9.2 ± 1.3 and 11.1 ± 1.5 in men (P < 0.001) and 9.1 ± 1.4 and 12.5 ± 2.2 in women (P < 0.001). Tidal volume distribution differed when using tidal volume/predicted body weight or tidal volume/actual weight (figs. 4and 5). Table 1lists the pre-, per-, and postoperative characteristics of the patients receiving low, traditional, and high tidal volumes as well as the organ failure frequency for each group.

The rate of organ failure increased with tidal volume, prolonged intubation (4.3%vs.  5.4%vs.  7.6%, P = 0.006), hemodynamic instability (5.4%vs.  7.9%vs.  10.1%, P = 0.001), and renal failure (7.9%vs.  10.4%vs.  12.7%, P = 0.004) for low, traditional, and high tidal volumes, respectively (table 1). In the univariate analysis, the presence of organ failure was associated with high tidal volumes (table 2). In the multivariate analysis, high tidal volume was an independent risk factor for organ failure and multiple organ failure (table 3), for mechanical ventilation lasting more than 24 h (high vs.  low: OR: 2.0 [1.12–3.44], P = 0.02) and hemodynamic instability (high vs.  low: OR: 2.4 [1.53–3.64], P = 0.007). Traditional tidal volume was an independent risk factor for hemodynamic instability (traditional vs.  low: OR: 1.8 [1.17–2.75], P < 0.001). An internal validation of the logistic model by bootstrap analyses demonstrated similar results.

Higher tidal volume was associated with longer stay in the ICU (2.0 ± 1.9 vs.  2.3 ± 3.2 vs.  2.7 ± 3.9 days, P < 0.001). High tidal volume was an independent risk factor for prolonged ICU stay of more than 48 h (high vs.  low: OR: 1.4 [1.17–1.79], P < 0.001) and more than 1 week (high vs.  low: OR: 1.8 [1.01–3.09], P = 0.04). There were no differences in hospital mortality and long-term mortality among the patient groups classified by tidal volume.

In the case of organ failure, the frequency of prolonged ICU stay and ICU mortality, hospital mortality, and long-term mortality increased (table 1, table 2, fig. 2).

The percentage of women who received low, traditional, or high tidal volumes was 14.6, 20.4, and 45.0%, respectively (P < 0.001). The mean body mass indexes (BMI) of the three groups were 24.3 ± 4.0, 27.0 ± 4.1, and 30.8 ± 5.1 kg/m², respectively (P < 0.001). In the multivariate analysis, a BMI of more than 30 kg/m²and female sex were risk factors when high tidal volumes were used (table 4).

In this observational study, we demonstrated the impact of tidal volumes used immediately after cardiac surgery on postoperative complications and patient outcomes. Traditional tidal volumes (10–12 ml/kg of predicted body weight) and high tidal volumes (more than 12 ml/kg of predicted body weight) were associated with prolonged mechanical ventilation, hemodynamic instability, renal failure, and prolonged stay in the ICU among patients who underwent cardiac surgery, compared with low tidal volumes (less than 10 ml/kg of predicted body weight). Use of high tidal volume was an independent risk factor for prolonged mechanical ventilation, hemodynamic instability, multiple organ failure, and prolonged ICU stay. Women and obese patients were more at risk of receiving injurious ventilation.

Tidal volume reduction is a standard of care for patients with ALI and ARDS.19There is no consensus for other patients, but some authors advocate broader applicability of protective ventilation.11Several studies have demonstrated a link between high tidal volumes and the development or aggravation of local and systemic inflammation in patients with normal lungs.8,9,13,20,–,22However, several studies did not observe such an effect.23,–,26The studies suggesting that tidal volume reduction has a protective effect included patients who underwent surgery with one-lung ventilation,7,8prolonged surgical procedures,9,20and cardiac surgery.13,21,22In a recently published paper by Kor et al.  it was shown that this latter group was at risk to develop early postoperative acute lung injury.27In the present study we showed that tidal volume was independently associated with patient outcomes after cardiac surgery. In this population, several studies showed that a protective ventilatory strategy can reduce systemic and pulmonary inflammation.13,21,22In a group of 40 patients who underwent coronary artery bypass graft surgery, Zupancich et al.  demonstrated that pulmonary and systemic proinflammatory cytokines levels increase in patients ventilated with high tidal volumes but not in those ventilated with low tidal volumes.13In a recently published study, Sundar et al.  compared ventilation with 10 versus  6 ml/kg tidal volumes after cardiac surgery.28The authors demonstrated that in the small tidal volumes group, fewer patients were intubated after 6 h, which may be related to the significantly higher PaCO²levels in this group. Also, fewer patients were reintubated in this group.28However, this study did not include enough patients to demonstrate differences on ICU length of stay, and data on organ dysfunction were not reported. It is likely that in the high tidal volume group, inflammation was increased as previously demonstrated.13Recently, it was demonstrated that increased inflammatory markers were independent predictors of major adverse cardiac events after cardiac surgery.29The present study is the first to demonstrate that high tidal volumes have an impact on cardiac surgery outcomes.

Although several studies have investigated the impact of high tidal volumes on lung dysfunction, few have evaluated the impact on other organs.11In the present study, high and traditional tidal volumes were associated with hemodynamic and renal failure. High tidal volumes have been associated with an increase in local and systemic inflammation and a decrease in mean arterial pressure compared with protective ventilation.13Another study has shown that protective ventilatory strategies decrease systemic and local inflammation, cardiac dysfunction, perivascular edema, and vascular congestion compared with high tidal volumes.30In the present study, both traditional and high tidal volumes were independent risk factors for hemodynamic instability. Renal failure can be induced by hemodynamic instability related to high tidal volumes31as well as by systemic inflammation as demonstrated in animal30,32studies. An injurious ventilatory strategy can lead to increased rates of epithelial cell apoptosis in the kidney and increased serum creatinine levels.32High tidal volumes can also result in reduced urine output and plasma creatinine clearance compared with protective ventilatory strategies.30 

We found that tidal volumes were independent predictors of prolonged ICU stays. To our knowledge, this is the first time that such a relationship has been reported in patients without ARDS. It must be acknowledged that the time when the patient is able to be discharged from the ICU and the time when the patient is actually discharged from the ICU may be different. We conducted analysis with both variables and found similar results. A prolonged ICU stay after cardiac surgery is associated with poor long-term outcomes and increased costs.33In the Kern et al.  study, 9% of the patients received more than 48 h of mechanical ventilation but accounted for 43% of the overall costs after cardiac surgery. In addition, mortality was 0.5% in patients ventilated for less than 48 h but rose to 11% in patients ventilated for more than 48 h.34Our results were similar to those of the Kern et al.  study in that the 202 patients (6%) ventilated for more than 48 h accounted for 2% of the number of days in the ICU, whereas mortality was 2.2% in patients ventilated for less than 48 h but rose to 42% in patients ventilated for more than 48 h.

In our study, patients with a high BMI were ventilated with a low tidal volume/actual body weight but a high tidal volume/predicted body weight. A similar pattern was recently reported with a large cohort of mechanically ventilated patients.35This underscores the need to use predicted body weight to set the optimal tidal volume in mechanically ventilated patients. Female sex was also an independent risk factor when high tidal volumes were used after cardiac surgery. Our results were in agreement with the study by Gajic et al. ,5in which women received higher tidal volumes than men and tended to develop more ALI. This may in part explain the results of previous studies reporting that female sex is a risk factor for prolonged mechanical ventilation after cardiac surgery.36 

There are several clinical implications of our findings. Our study provided an additional argument to promote the implementation of prophylactic protective ventilatory strategies, even in patients without ALI/ARDS. Many patients are exposed to possible causes of lung injury at admission37or during their ICU stay, including acquired sepsis,38transfusions,39ischemia, and reperfusion.40ALI/ARDS may occur several days after the beginning of mechanical ventilation, and the diagnosis is frequently underestimated. In the Herasevitch et al.  study, only 26% of the clinicians detected ALI/ARDS the day it occurred.41A multiple hit theory has been proposed by which repeated injuries lead to the development of ALI/ARDS.11Tidal volume reduction at the initiation of mechanical ventilation may prevent an additional “hit.” These results also demonstrate that some populations are at risk of being ventilated with high tidal volumes (obese patients and women), confirming that predicted body weight must be calculated and used to deliver protective ventilation.

Our study had a number of limitations. First, it was observational in design, as we did not randomize patients to different initial tidal volumes. Second, we compared different tidal volumes but did not evaluate PEEP. In most other studies, postsurgery protective ventilatory strategies combined high PEEP with low tidal volumes.8,9,13,20,–,22It is likely that tidal volume reduction should be delivered with a moderate increase in PEEP to prevent atelectasis, as with ARDS patients.42Third, the choice of tidal volume thresholds is open to discussion. In the nonparametric logistic regression showing the dose-response relationship between tidal volumes and organ dysfunction, three zones could be delineated, with different slopes for tidal volumes less than 10 ml/kg of predicted body weight and those more than 12 ml/kg (fig. 3). Schultz proposed 10 ml/kg of predicted body weight as the maximum tidal volume during mechanical ventilation.11Traditional tidal volumes (10–12 ml/kg) are in line with those recommended in widely used anesthesiology textbooks.14,15Fourth, it may not be possible to transpose our results to all patients. For example, in relatively young patients undergoing elective noncardiac surgeries, high tidal volumes have no impact on systemic or pulmonary inflammation after 126or 3 h.25These populations may not require the tidal volume to be adjusted, if no additional risk factors for acute lung injury are present. Also, it may be difficult to apply results of epidemiologic reports to individual clinical decision-making at the bedside. Multicenter randomized controlled studies are needed to confirm or refute these observations and to evaluate the external validity of the present results. Finally, we showed that the utilization of high tidal volumes is an independent predictor of organ dysfunction after cardiac surgery. However, an association and not a causality link could be demonstrated.

In conclusion, we found that traditional and high tidal volumes immediately after cardiac surgery are independent risk factors for organ dysfunction and prolonged ICU stay. Prophylactic protective ventilatory strategies should be provided in populations with an inflammatory state (virtually all critically ill patients) who are at risk of developing ventilator-induced lung injury. Women and obese patients are more at risk of being ventilated with injurious tidal volumes. As such, special care should be paid to ventilatory settings for these patients. In particular, predicted body weight rather than actual body weight should be used to set the tidal volumes in mechanically ventilated patients.