The role of continuous central venous oxygen saturation (ScvO₂) oximetry during pediatric cardiac surgery for predicting adverse outcomes is not known. Using a recently available continuous ScvO₂ oximetry catheter, we examined the association between venous oxygen desaturations and patient outcomes. We hypothesized that central venous oxygen desaturations are associated with adverse clinical outcomes.
Fifty-four pediatric patients undergoing cardiac surgery were prospectively enrolled in an unblinded observational study. ScvO₂ was measured continuously in the operating room and for up to 24 h post-Intensive Care Unit admission. The relationships between ScvO₂ desaturations, clinical outcomes, and major adverse events were determined.
More than 18 min of venous saturations less than 40% were associated with major adverse events with 100% sensitivity and 97.6% specificity. Significant correlations resulted between the ScvO₂ area under the curve less than 40% and creatinine clearance at 12 h in the Intensive Care Unit (r = -0.58), Intensive Care Unit length of stay (r = 0.56), max inotrope use (r = 0.52), inotrope use at 24 h (r = 0.40), inotrope index score (r = 0.39), hospital length of stay (r = 0.36), and length of intubation (r = 0.32).
We demonstrate that ScvO₂ desaturations by continuous oximetry are associated with major adverse events in pediatric patients undergoing cardiac surgery. The most significant associations with major adverse events are seen in patients with greater than 18 min of central venous saturations less than 40%. Our results support the further investigation of ScvO₂ as a potential target parameter in high-risk pediatric patients to minimize the risk of major adverse events.
What We Already Know about This Topic
Intermittent monitoring of central venous oxygen saturation, as a surrogate for mixed venous oxygen saturation, has been used as an index of global tissue perfusion and may predict adverse events following cardiac surgery
What This Article Tells Us That Is New
In this unblinded study, prolonged periods of venous desaturation on continuous oximetry were associated with increased adverse events in children with congenital heart disease who were undergoing cardiac surgery
PEDIATRIC patients undergoing cardiac surgery are at risk for adverse clinical outcomes in the perioperative period because of inadequate tissue perfusion. Although several clinical and laboratory markers associated with adverse clinical outcomes have been identified, the inability to readily and reliably assess global tissue perfusion and cardiac output remains a challenge in this patient group. Similar to results in adults, significant mixed venous (SvO2) desaturations seen with surgically placed oximeters have shown to be predictive of worsening neurologic function and clinical outcomes in neonatal patients undergoing palliative repair for hypoplastic left heart syndrome.1Unfortunately, mixed venous oximetry using percutaneous catheters is not feasible or practical in most children.
Central venous saturation (ScvO2), as a surrogate of SvO2, can reliably be used as a marker of global tissue perfusion. Recent studies have suggested the predictive power of intermittently measured ScvO2for adverse events following cardiac surgery.2,3However, intermittent or “snapshot” measurements of ScvO2are not able to assess the duration or temporal pattern of venous desaturations, and may not allow early detection of occult venous desaturations in the absence of other hemodynamic disturbances. Therefore, the true impact of desaturations on clinical outcomes is not clearly evident. In addition, though previous studies have suggested hemodynamics variables such as blood pressure, heart rate, and venous pressures to be poor predicators of adverse outcomes,1,4these variables remain a mainstay of critical care management in pediatric patients. Therefore, further investigation of the relationships between continuous ScvO2 and the more commonly used clinical hemodynamic and biochemical markers are needed to clinically interpret the value of continuous ScvO2monitoring in pediatric patients.
Using a newly developed, percutaneously placed continuous ScvO2oximetry system for children,5we examined the association between postoperative venous desaturations and clinical outcomes in pediatric patients undergoing cardiac surgery. We hypothesized that prolonged low central venous saturations are associated with adverse clinical outcomes.
Materials and Methods
Upon receipt of approval and informed consent from The University of California, Los Angeles Institutional Review Board, Los Angeles, California, 54 high-risk pediatric patients scheduled to undergo cardiac surgery with complete repair (no residual shunting), with or without cardiopulmonary bypass, and requiring a central venous catheter were consented for prospective data acquisition. Patient exclusion criteria included contraindications for a central venous catheter placement in the right internal jugular vein and body weight less than 3 kg.
Anesthetic induction consisted of inhaled sevoflurane and nitrous oxide, supplemented with intravenous fentanyl (3–5 μg/kg) and pancuronium (0.1 mg/kg). Isoflurane (1–1.5%) and fentanyl (10–15 μg/kg) were used to maintain anesthesia during the surgery. Following tracheal intubation, a central venous fiberoptic oximetry catheter (PediaSat™ oximetry catheter; Edwards Lifesciences, Irvine, CA) was calibrated in vitro and placed into the right internal jugular vein. Catheter size (4.5F/5 cm, 4.5F/8 cm, or 5.5F/8 cm) was determined according to patient size. Proper placement of the catheter tip at the lower portion of the superior vena cava and superior to the caval-atrial junction was verified by transesophageal echocardiography.
Following repair, patients received inotropic support as clinically indicated, including dopamine, dobutamine, epinephrine, and/or milrinone according to standard institutional protocols. Patients were transported to the Intensive Care Unit (ICU) and catheters were recalibrated on arrival in vivo with the most recent hemoglobin and venous blood gas co-oximetry values. Catheter tip location was reconfirmed with a chest radiograph and patients were monitored for clinical outcomes and major adverse events until the end of their hospital stay. All data were prospectively recorded.
Clinical Data Acquisition
In the Operating Room (OR), ScvO2, heart rate, central venous pressure, mean arterial pressure, arterial saturation, cerebral regional tissue oxygen saturation (rSO2) (INVOS® Cerebral Oximeter; Somanetics Corporation, Troy, MI), and core temperatures were recorded every minute. In the ICU, ScvO2and rSO2were recorded every minute, whereas heart rate, central venous pressure, mean arterial pressure, arterial saturation, and temperature gradients were recorded every 15 min. Data were recorded from the completion of surgical repair (if performed off cardiopulmonary bypass) or complete separation from cardiopulmonary bypass (if the procedure was performed on cardiopulmonary bypass) until 24 h after ICU admission. Data were collected until ICU discharge if patients were discharged before 24 h. In addition, ScvO2catheter measurements were compared to venous blood gas co-oximetry values of simultaneously drawn samples at predefined time points (OR baseline, prerepair, postrepair, chest closure, ICU admission, and 2, 4, 6, 8, 12, and 24 h postoperatively). Venous blood samples for co-oximetry measurement were drawn from the distal lumen of the catheter. Only those ScvO2catheter measurements with an adequate signal quality index from 1 to 3 were used. Serum lactate was measured at least every 6 h, or more frequently if indicated clinically. Serum creatinine measurements were drawn every 12 h. Complete rSO2data sets were acquired in a subset of 36 patients. For patients with bilateral cerebral rSO2sensors, the average was used for analysis. Postoperative clinical outcome data were prospectively recorded.
Major adverse events were defined as need for extracorporeal support, refractory cardiogenic shock or hypotension despite maximal medical therapy, sepsis, multi-organ dysfunction, and reoperation or reopening of chest in the first 24 h. We selected previously validated clinical outcome measures to assess the postoperative course of the study patients.6,–,8Total length of intubation, length of ICU stay, and length of hospital stay were measured in days for each patient. Creatinine clearance was calculated by the Cockcroft-Gault formula at 12 h post-ICU admission.9The maximum number of inotropes used during the study period, the number of inotropes still in use at 24 h, and inotrope score at 24 h were recorded. The inotrope score was calculated as described by Wernovsky et al. with dosages in micrograms per kilogram per minute: dosages of dopamine + dobutamine + (epinephrine × 100) + (milrinone × 10) at 24 h post-ICU admission.10
We investigated the frequency and temporal distribution of desaturation episodes detected by continuous ScvO2. For a given threshold ScvO2, we defined a desaturation episode as 5 or more consecutive min below the defined threshold, separated by 5 or more consecutive min above the threshold. These episodes were calculated for three separate time periods: from surgical repair/off cardiopulmonary bypass to OR discharge, first 12 h of ICU admission, and from 12 h following ICU admission until the end of data collection.
ScvO2Area under the Curve.
To relate intraoperative and postoperative ScvO2to clinical outcomes and hemodynamic or biochemical variables, we utilized the area under the curve (AUC) as a measure of degree of desaturation, where the area is calculated between a threshold ScvO2and the measured ScvO2values over time. The AUC is expressed as a product with the units of minute-percent and is determined as described below:
Y = measured ScvO2value, T = specified threshold value. We compute Z as the value of difference between the measured and specified threshold ScVO2according to the definition:
The AUC for each patient is calculated by the following formula: AUC = (ΣZ)*t, where t = total number of minutes from the end of surgical repair up to 24 h after ICU admission. The following threshold groups were selected for analysis: AUC 60–70%, AUC less than 60%, AUC less than 50%, and AUC less than 40%.
Time under Threshold and Receiver-operating Curve Analysis for Major Adverse Events.
We computed the time a patient remained under each threshold or between thresholds and, for each, determined the optimal time that best discriminates between those with major adverse events and without them. The optimal time was chosen by carrying out a nonparametric receiver operating characteristic curve analysis and was chosen such that accuracy was maximized. The accuracy was defined as the average of the sensitivity and specificity (accuracy = 0.5 sensitivity + 0.5 specificity). For the optimal time we report the sensitivity, specificity, accuracy, and positive and negative predictive values, assuming that the major adverse event prevalence is the same as in our data.
Correlation of ScVO2with Other Clinical Outcomes.
The associations of ScvO2AUC with clinical outcomes, standard hemodynamic measurements, and biochemical markers (lactate) were assessed using the Spearman rank test and by fitting restricted cubic splines. The nonparametric Spearman correlation and the corresponding splines using log scale AUC was used, because the relationship is not necessarily linear, even on the semilog scale. Using the spline fit, the average change in the outcome from the 25thto 75thpercentile change in each log ScvO2AUC was computed. This is essentially a nonparametric, robust slope. A P value <0.05 was considered statistically significant. Agreement between the catheter measured saturation and co-oximetry measured saturation values was assessed using Bland-Altman plot analysis.
Continuous data are presented as mean ± SD, or median with range as appropriate. Statistical analysis was performed with SPSS 16.0 (SPSS Inc., Chicago, IL) and SAS 9.2 (SAS Inc., Cary, NC).
Of the 54 patients enrolled, 3 patients were not included in the final analysis because of incomplete data sets caused by data storage errors. Another patient was excluded because of extracorporeal membrane oxygenation support being initiated in the operating room. Patient characteristics and surgical procedure for the 50 remaining patients are summarized in table 1. Given the diverse patient population, each patient's age, weight, preoperative diagnosis, and surgical procedure are provided in the appendix. No patient had a demonstrable intracardiac shunt on intra- and postoperative echocardiography regardless of undergoing single or bi-ventricular repair. Continuous ScvO2data were recorded from the end of surgical repair and up to the first 24 h postoperatively and lasted a median of 24 h (interquartile range 19.4–25.8 h). Only 2 patients were discharged from the ICU sooner than 24 h. There were no complications attributable to ScvO2monitoring or continuous data collection. Patient outcomes and clinical data are summarized in table 2.
Major adverse events were observed in 9 patients and are summarized in table 3. The sensitivity and specificity of ScvO2as a predictor for major adverse events were calculated using the time the ScvO2was less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, and from 60 to 70%. The accuracy of each time was calculated as the average of sensitivity and specificity. For the time with the greatest accuracy, the positive and negative predictive values for major adverse events were determined for various venous saturation thresholds and are summarized in table 4. Using receiver operating characteristic curve analysis, it was determined that a time greater than 18 min of ScvO2less than 40% was the most predictive for major adverse events with 100% sensitivity, 97.6% specificity, 98.8% accuracy, 90% positive predicative value, and 100% negative predictive value (fig. 1). Increasing time of ScvO2, such as less than 45% and less than 50%, were only slightly less predictive. A time greater than 93 min of ScvO2less than 55 percent was still highly predictive of major adverse events with an accuracy of 80.5%, a positive predictive value of 50%, and a negative predictive value of 97.1%. A ScvO2of less than 60% was only predictive of major adverse effects with a duration exceeding 13 h. ScvO2of 60–70% was not predictive of major adverse effects at any length of time. Using ScvO2AUC instead of time produced similar results.
Four ScvO2AUC groups were considered for analysis for correlation with clinical outcomes: AUC 60–70%, less than 60%, less than 50%, and less than 40%. These data are summarized in table 5. As AUC thresholds were decreased in 10% increments from AUC 60–70% to AUC less than 40%, an increasing number of associations with clinical outcomes were observed. At ScvO2AUC less than 40%, significant correlations were found between creatinine clearance at 12 h postoperatively (r = −0.58), length of ICU stay (r = 0.56), maximum number of inotropes used (r = 0.52), number of inotropes used at 24 h (r = 0.40), inotrope index score at 24 h post-ICU admission (r = 0.39), length of hospital stay (r = 0.36), and length of intubation (r = 0.32). Statistically significant, but slightly weaker, correlations resulted between ScvO2AUC less than 50% and creatinine clearance 12 h postoperatively (r = −0.56), length of ICU stay (r = 0.44), max inotrope use (r = 0.39), inotrope use at 24 h (r = 0.33), length of hospital stay (r = 0.30), and inotrope index score (r = 0.30). Significant correlations were observed only between AUC less than 60% and creatinine clearance 12 h postoperatively (r = −0.52), length of ICU stay (r = 0.33), and length of hospital stay (r = 0.32).ScvO2AUC 60–70% was not significantly correlated with any of the clinical outcomes.
In addition to the correlation of ScvO2AUC and clinical outcomes, the magnitude of effect of increasing AUC and the change in the outcome measure was determined between the 25thand 75thpercentile in each ScvO2AUC range. For a ScvO2AUC less than 40%, length of intubation increased by 1.43 days, length of ICU stay increased by 4.32 days, length of hospital stay increased by 1.93 days, maximum inotrope use increased by 1.01, inotrope use at 24 h increased by 0.74, the inotrope index score increased by 6.05 mcg/kg/min, and creatinine clearance at 12 h decreased by 24.53 ml/min. For an ScvO2 AUC less than 50%, the length of ICU stay increased by 6.01 days, length of hospital stay increased by 6.9 days, the maximum inotrope use increased by 0.76, the maximum inotrope use at 24 h increased by 0.54, the inotrope index score increased by 3.79 mcg/kg/min, and the creatinine clearance at 12 h decreased by 26.93 ml/min. The ScvO2 AUC less than 60% demonstrated an increase in the length of ICU stay and hospital stay by 4.98 and 5.44 days, respectively, and a decrease in creatinine clearance at 12 h of 15.33 ml/min.
Desaturation episodes were calculated for ScvO2thresholds of less than 40%, less than 50%, less than 60%, and less than 70%, and are summarized in table 6. The highest number of observed desaturation episodes occurred within the first 12 h after surgical repair.
Regression analysis demonstrated no significant association between ScvO2measurements and hemodynamic variables such as blood pressure, heart rate, and central venous pressure (P > 0.05) in the ICU. Core temperature and temperature difference also did not correlate with ScvO2. In addition, calculated AUC for greater than 25% change in mean arterial pressure or heart rate from clinically normal values for age11were not significantly associated with any clinical outcome.
Though serum lactate was found to not correlate with ScvO2AUC at any threshold, lactate levels proved to be an independent predictor of poor outcomes, demonstrating an association with creatinine clearance 12 h post-ICU admission (r = −0.4), length of ICU stay (r = 0.4), length of hospital stay (r = 0.4), inotrope use at 24 h (r = 0.4), inotrope index score (r = 0.4), and max inotrope use (r = 0.3).
In the subset of 36 patients in whom rSO2AUC was recorded in addition to ScvO2AUC, rSO2and ScvO2were found to be significantly correlated in the OR (r = 0.51) and ICU (r = 0.3). rSO2AUC less than 40% was significantly correlated with creatinine clearance (r = −0.48) and length of ICU stay (r = 0.40). Fewer significant associations were seen with rSO2AUC less than 50%, which correlated with only length of ICU stay (r = 0.39).
The accuracy and precision of the pediatric ScvO2oximetry system was monitored throughout the study. Bland-Altman plot analysis of 341 paired data sets of venous blood gases and ScvO2catheter simultaneous measurements showed difference of means (bias) and precision to be 0.41%± 4.93%, respectively.
Our investigation demonstrates that low perioperative ScvO2is associated with poor clinical outcomes in pediatric patients undergoing cardiac surgery. This is the first study to demonstrate that pediatric patients with a larger area under the curve of continuous ScvO2saturation below 40% had increased length of intubation, stay in the ICU, stay in the hospital and inotrope use, along with lower creatinine clearance in the perioperative period. An AUC less than 50% proved to be almost equally associated with poor clinical outcomes. An AUC less than 60% had weaker association with poor clinical outcomes, whereas AUC 60–70% had no significant associations.
Furthermore, ScvO2was also an excellent predictor of major adverse effects. Our results from receiver operating characteristic curve analysis demonstrate that periods as brief as 18 min below saturation of 40% are highly predictive of major adverse effects. We observed that venous saturations of less than 50% for greater than 34 min are also significantly predictive of major adverse effects. The data also show that more mild venous desaturations are well tolerated for significantly longer periods of time, without increasing the risk of major adverse effects. In addition, ScvO2values at various thresholds maintained a strong negative predictive value, demonstrating that avoidance of lower venous saturations is a valid goal in pediatric patients undergoing cardiac surgery to decrease the risk of major adverse events.
Our findings indicate that the largest incidence of significant ScvO2desaturations predominantly occur within the first 12 h postoperatively. During these periods where ScvO2fluctuations are commonly anticipated, continuous ScvO2monitoring, rather than intermittent venous sampling, would be extremely valuable for detection of venous desaturations to prompt earlier interventions. Finally, ScvO2with fiberoptic oximetry was accurate with a low bias and good precision (0.41%± 4.93%), supporting the potential use of continuous ScvO2as a reliable target parameter in high-risk pediatric patients.
The clinical value of ScvO2monitoring was originally proposed in patients with cardiac disease in 1970.12Adult clinical trials have suggested that low ScvO2saturations are associated with increased risk of mortality and independently associated with poor clinical outcomes. Suggested target ScvO2values from these studies ranged from 60 to 73%.13,–,22Surprisingly limited such data exists for pediatric congenital heart disease patients, and clinical practice is often dictated by experience from adult studies. Our results suggest that increasingly poor clinical outcomes are seen with ScvO2less than 60%, with significantly worse outcomes present with ScvO2less than 40%. However, poor correlations were found between continuous ScvO2and commonly measured hemodynamic variables, suggesting that ScvO2better reflects global cardiopulmonary changes and tissue perfusion. This observation is also supported by previous experimental findings demonstrating that decreases in ScvO2can reflect tissue hypoxia despite apparently normal hemodynamic parameters.1,5
While no study to date has investigated the relationship of lactate elevation resulting from anaerobic conditions and continuous ScvO2, several pediatric studies have found that lactate was an independent predictor of poor clinical outcomes.2,23–24Our results agree with these findings in that higher lactate measurements were associated with longer stays in the ICU and hospital, higher inotrope use, and lower creatinine clearance postoperatively. It is not unexpected that of the other measured physiologic parameters, ScvO2would be most correlated with rSO2, because the two parameters are affected by similar physiologic principles governing oxygen delivery. However, correlations in the ICU were much weaker when compared with those in the OR. In the 35 patients with complete rSO2data sets, significant associations were also observed between rSO2AUC and clinical outcomes; these associations were not as significant as those seen with ScvO2. This difference may be due to a more pronounced influence of pCO2on rSO2values, whereas ScvO2values are largely independent of ventilation. In part, the weaker association between rSO2and clinical outcomes may also be because of the assumptions incorporated into the algorithms used in the monitoring technology (site of measurement in forebrain), or because of the variability incurred as a result of altering sensor contact on the forehead when placed for extended periods. This also may be a statistical phenomenon because there were fewer patients with complete rSO2data sets.
Continuous fiberoptic venous oximetry in pediatric patients has recently been shown to be accurate and poses minimal additional risks compared with standard central venous catheter placement.5,25In the presence of tissue hypoxia, continuous monitoring of ScvO2may allow for detection of decreased tissue oxygen delivery earlier in comparison to traditional, and typically late, indicators of organ dysfunction, such as increased lactate, decreasing urine output, and increasing metabolic acidosis. Real-time information about tissue oxygenation in pediatric patients can have a profound impact in decreasing morbidity by detecting tissue hypoperfusion earlier than other hemodynamic and chemical parameters. In addition, the use of a real-time perioperative ScvO2monitor is particularly useful in pediatric patients to decrease the number of blood draws required for venous saturation monitoring. Since the monitoring of continuous ScvO2saturations is accurate, uses a parameter familiar to critical care physicians, and has no further risk to the patient than standard central venous catheter placement, it would seem a logical step to add this monitor to standard perioperative care in high-risk pediatric patients. Clinical utilization of continuous ScvO2monitoring should continue to take into account the complexity of the patient's surgical repair, other hemodynamic parameters, and biochemical monitors to make a comprehensive assessment.
While the findings of our investigation are promising, we acknowledge several limitations. Our study was an observational, unblinded prospective trial, and although poor clinical outcomes and major adverse events strongly correlated with ScvO2less than 40% and 50%, a prospective trial to evaluate the utility of continuous ScvO2as a target parameter of goal-directed therapy to improve clinical outcomes is warranted. Technical limitations of the ScvO2catheter were minimal from our experience and included wall artifacts caused by impingement of the catheter tip on a vessel wall that led to an unreliable signal, as detected by a signal quality index value of 4. In all cases, repositioning of the catheter resulted in restoration of an appropriate signal. Although the study was not blinded, the practice in our ICU before the study and the study protocol required therapeutic interventions to be made primarily using confirmed venous desaturations from intermittent venous blood gas samples and/or other clinical indicators. There is some possibility that bias might have been introduced with the presence of the monitor and that the information could have been used to guide therapy. The availability of continuous venous oximetry may have influenced some of the clinical outcomes, such as escalation of inotropes, delayed extubation, or delayed discharge. However, the unblinded nature of the study should not have influenced the occurrence of major adverse events or parameters such as creatinine clearance. In addition, there was no treatment algorithm provided for the treatment of low continuous ScvO2and the physicians involved in the study were not obligated to use the continuous ScvO2values to guide therapy. The fact that the information was available to the treating physicians, but that significant adverse outcomes were still observed, may be demonstrative that even more aggressive intervention needs to be undertaken to resolve low venous saturations in a timely fashion.
In summary, our prospective observational study demonstrates a significant association between intraoperative and postoperative ScvO2desaturations and unfavorable clinical outcomes in pediatric patients. Further investigation should focus on quantifying ScvO2temporal responsiveness to changes in standard hemodynamic parameters and defining target ScvO2levels specific to patient groups as part of a blinded clinical trial.
The authors thank Jeffery Gornbein, Ph.D., Professor, Department of Biostatistics, University of California-Los Angeles, Los Angeles, California, for performing the statistical analysis used in the study and Jennifer Scovotti, M.A., and Cecilia Canales M.S. (Research Associates), Department of Anesthesiology, University of California-Los Angeles, for helping with the data collection.