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Perioperative goal-directed hemodynamic therapy based on radial arterial pulse pressure variation and continuous cardiac index trending reduces postoperative complications after major abdominal surgery: a multi-center, prospective, randomized study
Critical Care 2013, 17:R191 doi:10.1186/cc12885

Cornelie Salzwedel (c.salzwedel@uke.de) Jaume Puig (jaupuig1@gmail.com) Arne Carstens (arne.carstens@uksh.de) Berthold Bein (berthold.bein@uksh.de) Zsolt Molnar (z_molnar@hotmail.com) Krisztian Kiss (krisztian.kiss.md@gmail.com) Ayyaz Hussain (ayyaz@mail.ru) Javier Belda (fjbelda@uv.es) Mikhail Y Kirov (mikhail_kirov@hotmail.com) Samir G Sakka (sakkas@kliniken-koeln.de)

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1364-8535 Research 19 April 2013 2 August 2013 8 September 2013 http://ccforum.com/content/17/5/R191

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Perioperative goal-directed hemodynamic therapy based on radial arterial pulse pressure variation and continuous cardiac index trending reduces postoperative complications after major abdominal surgery: a multi-center, prospective, randomized study
Cornelie Salzwedel1,† Email: c.salzwedel@uke.de Jaume Puig2,† Email: jaupuig1@gmail.com Arne Carstens3 Email: arne.carstens@uksh.de Berthold Bein3 Email: berthold.bein@uksh.de Zsolt Molnar4 Email: z_molnar@hotmail.com Krisztian Kiss4 Email: krisztian.kiss.md@gmail.com Ayyaz Hussain5 Email: ayyaz@mail.ru Javier Belda2 Email: fjbelda@uv.es Mikhail Y Kirov5 Email: mikhail_kirov@hotmail.com Samir G Sakka6 Email: sakkas@kliniken-koeln.de Daniel A Reuter1* * Corresponding author Email: dreuter@uke.de)
1

Department of Anesthesiology, Center of Anesthesiology and Intensive Care Medicine, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany

200. Arkhangelsk 163061. CG: 180 minutes. Avinguda de Blasco Ibáñez. University Hospital Schleswig-Holstein. and mean arterial pressure in a study group (SG). . 51 Troitsky Prospect. Russian Federation 6 Department of Anesthesiology and Operative Intensive Care Medicine. 17. Outcome data were recorded up to 28 days postoperatively. p = 0. Germany † Equal contributors.038). In the SG hemodynamic therapy was guided by pulse pressure variation.Department of Anesthesia and Critical Care. Medical Centre Cologne -Merheim.516) or length of hospital stay (SG: 11 vs. 46010 Valencia. reduced length of hospital stay and quicker return of bowel movement postoperatively in abdominal surgical patients. p = 0. Campus Kiel. CG: 2 days postoperatively. cardiac index trending by radial artery pulse contour analysis. We hypothesized that using a treatment algorithm based on pulse pressure variation. Germany 4 Department of Anesthesiology and Intensive Therapy. p = 0. Northern State Medical University. University Witten/Herdecke.316). 52 complications. In the CG hemodynamic therapy was performed at the discretion of the treating anesthesiologist. Spain 3 2 Department of Anesthesiology and Intensive Care Medicine. Hungary 5 Department of Anesthesiology and Intensive Care Medicine. Hospital Clínico Universitario. Abstract Introduction Several single-center studies and meta-analyses have shown that perioperative goal-directed therapy may significantly improve outcomes in general surgical patients. Results The total number of complications was significantly lower in the SG (72 vs.023). Methods 160 patients undergoing elective major abdominal surgery were randomized to the SG (79 patients) or to the CG (81 patients). 6725 Szeged. 51109 Köln. infection complications were significantly reduced (SG: 13 vs. p = 0. Ostmerheimer Str. CG: 26 complications. University of Szeged. duration of post anesthesia care unit stay (SG: 180 vs. University of Valencia. p = 0. CG: 10 days. cardiac index trending and mean arterial pressure.929). Arnold-Heller-Straße 3. when compared to a control group (CG). 24105 Kiel. Semmelweis St.. There were no significant differences between the two groups for return of bowel movement (SG: 3 vs. would result in reduced complications. In particular. 6.

All these studies were single-center studies which makes the meta-analysis that dealt with these highly divergent studies hard to interpret [9].24]. GDT based on PPV has also been shown to improve patient outcome [23.Conclusions This multi-center study demonstrates that hemodynamic goal-directed therapy using pulse pressure variation. if it occurs due to rapid surgical changes such as sudden blood loss. such as heart rate and mean arterial pressure (MAP) remain relatively unchanged despite reduced blood flow and are therefore considered insensitive indicators of hypovolemia [10] or changes in cardiac index (CI) [11]. reflecting the cyclic changes in preload induced by mechanical ventilation. and orthopedic surgery [8]. thus enabling the avoidance of unnecessary and potentially harmful volume loading [17-22].g. but also in trauma [6. the perioperative mortality rate is still higher than expected [1]. Cardiac output. Trial registration NCT01401283. Further. Although these devices show lower precision compared to the clinical gold standards of thermodilution. based on the titration of fluids and inotropic drugs to physiological flow-related end points. less invasive devices assessing CO by pulse contour analysis based on the radial artery pressure signal have been introduced [12-15]. their ability to adequately assess changes in CO is promising [16]. is to reduce perioperative complications which might even help to reduce perioperative morbidity and mortality [2]. it can be corrected quickly. adequate oxygen supply can be maintained intraoperatively. or less invasively. Keywords Complications. Multiple single-center studies have shown that perioperative GDT may significantly improve outcome. Volume therapy. cardiac index trending and mean arterial pressure as the key parameters leads to a decrease in postoperative complications in patients undergoing major abdominal surgery. Goal-directed therapy. GDT is targeted to detect hypovolemia and hypoperfusion early in order to make a quick response possible. The aim of goal-directed hemodynamic therapy (GDT). with the esophageal Doppler.7]. Oxygen debt can be avoided or. pulse pressure variation (PPV). has shown to accurately reflect volume responsiveness in a number of different high risk surgical groups. including the pulmonary artery catheter or using transpulmonary thermodilution. . The underlying physiological rationale of GDT is that due to improved cardiovascular function. Routine hemodynamic measurements. cardiac output (CO) has traditionally been associated with the use of additional invasive monitoring. Measurement of blood flow. Stroke volume Introduction Despite high standards in surgical and anesthetic care in Europe. e. Recently. particularly in patients undergoing abdominal surgery [3-5].

Hungary). prospective. CI and MAP. Inclusion criteria were an anticipated duration of surgery of more than 120 minutes or an estimated blood loss of more than 20% of blood volume. Germany). It was registered at clinicaltrials. This arterial line was additionally connected to the cardiac index trending monitor (ProAQT. Spain). controlled trial between August 2011 and May 2012. PULSION Medical Systems SE. as shown in Figure 1a. Intraoperative management Study group Patients of the SG received basic anesthetic monitoring by 5-lead-electrocardiogram. randomized. patients received an initial hemodynamic assessment based on PPV. and arrhythmias. Materials and methods This study was conducted as a multi-center. at least one peripheral i. It was approved by the appropriate Institutional Review Boards of all participating centers and conforms to the Journal’s requirements for human trials. Patient enrollment. First. We hypothesized that following this treatment regimen results in reduced postoperative complications (primary endpoint) and reduced length of hospital stay (secondary endpoint).We conducted this trial as a multi-center study with the inclusion of a large variety of surgical interventions and patient groups. Germany).. and an indication for an arterial line and central venous catheter. Enrollment. At the beginning of surgery. Exclusion criteria were a planned postoperative high-care intensive care unit stay. a central venous catheter and invasive radial arterial blood pressure monitoring. Russia). Standard perioperative care of abdominal surgical patients was compared with hemodynamic management based on PPV and continuous CO trending using radial artery pulse contour analysis. University Hospital Schleswig-Holstein. For risk evaluation. Written informed consent was obtained from all subjects. Germany).gov with the registration number NCT01401283. laparoscopic surgery. Care providers and investigators could not be blinded due to the presence of the cardiac index trending monitor. pulse oximetry and blood pressure cuff. University of Szeged (Szeged. Only patients were blinded to group allocation. Hospital Clínico Universitario de Valencia (Valencia.v. preload was optimized . ASA classification [25] and Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (POSSUM) [26] were documented. (Kiel. pregnant or lactating woman. American Society of Anesthesiology (ASA) classification 2 or 3. Munich. sequence generation and assignment to interventions were performed by a responsible investigator of each participating study center. gynecological and urological surgery were recruited. Patients Patients undergoing elective abdominal surgery including general. University Hospital Hamburg-Eppendorf (Hamburg. using serially numbered opaque envelopes. randomization and blinding Patients were randomized either to the study group (SG) or the control group (CG). Patients were recruited in five centers: Northern State Medical University (Arkhangelsk.

Data on catecholamine use and on estimated blood loss. central venous pressure and heart rate were recorded.5 l · min-1 · (m2)-1. as described in Additional file 1..v. as patients in the control group did not receive cardiac index trend monitoring. Endpoints Primary endpoint Pre-defined postoperative complications for each patient (see Additional file 1) were recorded for up to 28 days after surgery from patient record and by visiting patients on the ward by the investigators. Patients were ventilated using tidal volumes of 8–10 ml/kg of ideal body weight. Control group Patients of the CG received basic anesthetic monitoring by 5-lead-electrocardiogram. Postoperative management All patients were monitored in the post anesthetic care unit (PACU) until they were transferred to the ward. Data collection and collection of blood samples for complete blood gas analysis was identical to that of the study group. At the beginning and at the end of surgery blood samples were drawn for arterial and central venous blood gas analysis. urine output and infused fluids were obtained 24 hours postoperatively. The types and clustering of complications were predefined in the study protocol. patients were reassessed every 15 minutes intraoperatively to maintain values according to the study algorithm as illustrated in Figure 1b. at least one peripheral i. vasopressors were started. At this point the patient’s individual preload optimized CI was determined and used as the hemodynamic goal until the end of surgery. After the initial assessment. inotropes were applied to reach this minimum CI. If PPV and CI were within the target range but MAP was below 65 mmHg. Figure 1 Hemodynamic treatment algorithms: a) Algorithm for initial assessment and treatment. postoperative complications and duration of postoperative hospital stay were recorded for up to 28 days after surgery. Every 15 minutes MAP. Arterial and central venous blood gas analyses were drawn on discharge from recovery and duration of stay in the PACU was recorded in minutes. b) Algorithm for further intraoperative optimization. urine output and infused fluids were recorded. ventilatory parameters every 60 minutes. Treatment of patients in the CG was entirely performed on the discretion of the care-giving anesthesiologist. pulse oximetry and blood pressure cuff. At the end of surgery total catecholamine administration. serving as a safety-parameter to prevent patients from low cardiac output. need for enteral feeding. Only if this value was below 2. The time between the end of surgery and extubation was recorded. Hemodynamic data were documented every 30 minutes. except for PPV and CI. estimated blood loss. a central venous catheter and invasive radial arterial blood pressure monitoring. .by fluid loading until PPV was <10%. Return of bowel function.

Statistical analysis Sample size calculation was oriented on previously reported data in a comparable single center study on 33 patients [24]. For continuous data. the power analysis based on a reduction of complication rate from 40 to 20%. pointing towards an actual complication rate of around 40% in this patient population in our centers. USA). Complication rate in this study was 75% in the control group and 41% in the intervention group. Data were analyzed using Sigma Stat 3. types of surgery and duration of surgery did not differ significantly between the two groups. . Categorical data were compared using χ2 and Fisher’s exact tests. listed in Additional file 2. Results A total of 180 patients were randomized. 20 patients had to be excluded from the study and/or analysis because of various reasons. Preoperative risk scores.5 and SigmaPlot 10 (Systat Software Inc. Comparison of intraoperative data was restricted to the duration of 5 hours.05 This revealed a group size of 80 patients per arm. ranging from 17 to 43 from each of the five study centers. the data were analyzed with the Student’s t-test.05 was defined as statistically significant. Non-parametric data were analyzed with the Mann–Whitney U-test. We compared those data with routinely derived data from our study sites. and statistical significance of p < 0. 79 patients in the SG and 81 patients in the CG were included in the final analysis. Demographic data are given in Table 1.. A level of p <0. where appropriate. taking in account a power of 80%. the Kolmogorov-Smirnov tests were performed to assess normal distribution and.Secondary endpoint Length of hospital stay in days was obtained from patient record. San Jose. where 75% of surgeries were finished. Data are given in mean ± standard deviation or Median [interquartile range] as appropriate. Recruitment for the trial ended after the inclusion of the required 160 patients for analysis. Therefore.

001).2 ± 18. ABW = actual body weight.1 64. CG: 75. p = 0. p = 0.9 mmHg.4 0.7% mmHg vs.8 221.0 ± 10.7% mmHg.899 Height* [cm] 171.4 0. CG: 74. POSSUM = Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity.7% mmHg vs. CG: 83.8 ± 19. Fluids and catecholamines Fluid balance There were no significant differences in the net amount of fluids administered intra. Values are given in Table 2.595).002).3 mmHg. Intra.5 + 0. χ2-test or Fisher’s exact test as appropriate to detect potential preoperative differences between the two groups. 45 minutes (SG: 83.4).4).9 ± 14. MAP was significantly lower in the CG on arrival to the PACU (SG: 90. Also urine output and blood loss did not differ between both groups.765 Male : female 50 : 31 47 : 32 0.1% mmHg.5 ± 16.3 ± 16.91*(height[cm]-152. p = 0.9 ± 86.9 ± 16. Figure 2 Mean arterial pressure intraoperatively. These differences are illustrated in Figure 2 and exact values are given in Additional file 3. CG: 88.1 ± 15.024).3 ± 10.4% mmHg vs. p = <0.6 ± 14.Table 1 Demographic data Study group (n = 79) p-value Control group (n = 81) Age° [years] 65 [18.978 POSSUM physiological° 17 [7] 16 [5] 0.and postoperative hemodynamic parameters MAP differed significantly at 30 minutes (SG: 81. 120 minutes (SG: 81.5 ± 20.241 ABW* [kg] 79.75] 0. p = 0.332 Duration of sugery [minutes] 237.0 ± 15. No specific complications or harm due to the use of the hemodynamics trending monitor or to the application of the study algorithm could be observed. . There were no differences in MAP on discharge from PACU (SG: 90.4 ± 20.5% mmHg. p = 0. PBW = predicted body weight: PBWmale = 45.557 PBW* [kg] 66.2 0.7 ± 9.8 ± 19. ASA = physical status classification system by the American Society of Anesthesiologists.1 ± 15.025) intraoperatively.4 mmHg vs.012) and 150 minutes (SG: 79. Mann–Whitney U-test.2% mmHg vs.332 Non-bowel 40 32 0.1 0.921 POSSUM operative° 17 [9] 15 [8.4 170 ± 9.321 Data are mean ± SD* or median [IQR]°.91*(height[cm]-152.0 mmHg vs. Postoperatively.5 ± 109. CG: 74.269 ASA III 33 33 0.4% mmHg. CG: 73.067 Type of surgery [number of patients] Bowel 41 47 0. Data were compared using Student’s t-test. PBWfemale = 50 + 0.0 ± 14.1 77.and postoperatively.25] 63 [17] 0.

6 3854.2 ± 676.5 ± 620.8 3296.376 0.6 ± 211.2 141. . CG: 42 patients.501 0. CG: 9 patients.6 73.0 ± 1216.521 0.470 0.3 ± 1134.5 ± 2469.4 3635. p = 0. None of the patients received inotropes after the end of surgery.6 3260. the number of patients receiving vasopressors was equal between the two groups (SG: 42 patients vs.8 724.9 3956.3 2862.0 ± 1871.4 ± 324.7 4332.502).4 ± 1036.8 ± 164.4 3404.0 268.1 249.and postoperatively Control group (n = 81) Fluids intraop [ml] Blood loss Urine output Crystalloids + Colloids Crystalloids Colloids FFP PRBC Input total Fluid balance Fluids postop [ml] Blood loss Urine output Crystalloids + Colloids Crystalloids Colloids FFP PRBC Input total Fluid balance Fluids total [ml] Input Crystalloids Colloids Balance 704.4 3452.7 ± 371.6 7053.5 85.6 462.2 962. Data were compared using Student’s t-test.425 0.990 0.4 ± 376.9 ± 2598.2 ± 4906.561 Data are mean ± SD.7 3204.8 ± 2104.7 0±0 44.2 7597.8 ± 2051.829 0.8 1679.3 ± 189.Table 2 Fluids intra. Vasopressors and inotropes As listed in Table 3.8 ± 2827.7 p-value 0.6 ± 705.2 ± 1954.2 ± 3285.078 0.2 1724.773 0.0 ± 379.373 0.994).555 0.9 56.6 ± 307. compared to none in the CG (p < 0.5 ± 2792.001).8 5876.656 0.7 Study group (n = 79) 668.6 960.0 773.7 ± 1592.6 ± 388.9 ± 2374.6 ± 3715.764 0.7 ± 664.333 0.498 0.0 ± 473.2 34.0 ± 2138.2 2680.369 0.4 3724.5 2604.7 ± 720.2 ± 2584.2 3598.346 0.3 ± 862.2 ± 2110.7 ± 252.780 0.477 0.2 146. FFP = Fresh frozen plasma. p = 0.3 6031.4 144.9 ± 1694.1 1677.988 0.2 2813. Few patients required vasopressors postoperatively with no significant difference between the two groups (SG: 5 patients vs.2 ± 1153.6 414.7 ± 924.8 ± 2325.2 ± 2283.2 224.191 0.5 3770.3 ± 1438.2 1357.4 ± 889. PRBC = Packed red blood cells. 33 patients in the SG received inotropes during surgery.

0 ± 7.8% vs.1%. compared to 36 (44.2 ± 8. Figure 4 Number of patients with complications bowel vs. CG: 12 patients.3. p = 0. Also. at the end of surgery (SG: 80.003) compared to non-bowel surgery (SG: 9 patients vs. CG: 26 complications.4 vs. In the SG.01). CG: 18 complication. see Figure 4. CG: 98. p = 0.9 ± 8.502 Oxygenation There were no differences in peripheral oxygen saturation between the two groups before surgery (SG: 98.023).328). . as illustrated in Figure 3a. and on discharge from PACU (SG: 73. p = 0.0.Table 3 Use of inotropes and vasopressors Control group (n = 81) Inotropes intraop * Dobutamine Vasopressors intraop * Total Norepinephrine Phenylephrine Ephedrine Inotropes postop * Dobutamine Vasopressors postop * Norepinephrine * [number of patients].6%) of patients had at least one complication. 0 40 32 4 8 0 9 Study group (n = 79) 33 37 26 0 11 0 5 p-value <0.2 ± 1.1 ± 2. no bowel surgery.307). p = 0. p = 0.9 vs. p = 0. as illustrated in Figure 3a. p = 0.994 0. Analysis of the predefined clustering of complications showed that there was a significant difference in the subgroup of infection complications (SG: 13 complications vs.931).977).4 ± 2. p = 0. but without reaching statistical significance. Further. p = 0. CG: 82.5%.7%.905).649). Complications The overall number of complications was significantly lower in the SG (52 complications vs. p = 0.482 0. p = 0. 29 complications.038). b) number of patients with complications. at the end of surgery (SG: 98.9% vs. a) number of complications.1 ± 2.9 ± 7. CG: 24 patients.440). The reduction in the number of patients with complications was particularly pronounced in the group of patients receiving bowel surgery (SG: 12 complications vs. CG: 98. Analysis of clustering of complications showed that the number of infection complications in patients undergoing bowel surgery was significantly reduced (SG: 8 complications vs. CG: 80.028).001 0. there was a significant difference in the total number of patients with complications.5% vs. as depicted in Figure 3b.1%. Also the cluster of abdominal complications showed a trend towards less complications in the SG (22 complications vs. CG: 97. 72 complications.9 vs.4%) in the CG (p = 0.7 ± 2.584 0.2 ± 1.126) and at discharge from recovery (SG: 96.135 0.8 ± 7.2 ± 8. p = 0. CG: 73. central venous saturation did not show any statistically significant difference before surgery (SG: 82. Figure 3 Postoperative complications. We further analyzed the subgroup of patients that received bowel surgery compared to nonbowel surgery. 21 (26.

929) in the two groups. however. Further. as well as for the healthcare system. including patients’ preoperative fitness and health. These diverse studies with different study protocols and algorithms make comparison and common evaluation very difficult.Outcome There were no significant differences in the return of first bowel movement after surgery (SG: 3 [1] days vs. p = 0. CG: 8 patients. However. However. This strengthens the results of previous single-center studies [4.23. current meta-analyses [29-31] and a recently published Cochrane review [32]. Results are very much in-line with the results of the multi-center study presented here. Discussion This is the first randomized multi-center study in patients undergoing major abdominal surgery demonstrating that perioperative hemodynamic GDT using pulse pressure variation. The study showed a significant decrease in the primary endpoint (complications) for patients in the study group. CG: 180 [114] minutes. Several single-center studies and meta-analyses have already pointed towards the benefit of perioperative hemodynamic GDT on patient morbidity and mortality. length of hospital stay is one important factor for the individual patient. the number of patients with complications was significantly reduced by the intervention [32]. there were no significant differences in the duration of stay in the PACU (SG: 180 [127.8] days.316) and the need for enteral feeding postoperatively (SG: 5 patients vs. The review analyzed randomized controlled single center trials on the intervention of increasing perioperative blood flow using fluids with or without inotropes or vasoactive drugs to defined goals in adults. the intention of our study was to investigate the influence of GDT in different medical centers in different countries. it is obvious that it is affected by many aspects besides postoperative complications. radial artery pulse contour cardiac index and mean arterial pressure as its key parameters leads to a reduction in postoperative complications. We chose postoperative complications as the primary outcome parameter because the occurrence of 28-day postoperative complications has been shown to be of greater importance than preoperative patient risk and intraoperative factors in determining survival after major surgery [27]. p = 0. p = 0.28]. Therefore. Undoubtedly.5. There was no difference in mortality between the CG and the treatment group. . and also a reduction in the number of patients with complications.24. respiratory failure and wound infections was significantly reduced in the treatment group.595). CG: 10 [11. p = 0. but also the social. a single-center study always has the potential limitation that it is performed by a highly skilled study team – this of course strengthens the quality of data. with different local practices and a broad range of different intra-abdominal procedures. structural and logistical aspects of each individual patient and each health care system. Furthermore.516) or length of hospital stay (SG: 11 [8] days vs. the rate of renal failure. Also. potentially it does not test the adoption of the protocol into daily clinical practice. In order to keep this diversity and therefore allowing its translation in daily clinical routine we did not dictate treatment in the control group. CG: 2 [1].5] minutes vs.

showed a reduction in postoperative complications after the use of GDT postoperatively owing to an increase in global oxygen delivery through volume optimization and inotropic therapy. However. [35] conducted a double-blinded. the power of this study is not sufficient to draw this final conclusion. standard fluid regimen with the subgroups of aerobically fit and unfit patients. where current clinical guidelines recommend perioperative ß-blockade as cardioprotection [37]. Further research needs to be directed at high risk patients undergoing major. In some cases this results in a combination of a healthy. if the indication for inotropes is increased on the basis of these findings. although patients from both groups received nearly the same net amount of fluids perioperatively. The subgroup of aerobically fit patients consisted mainly of ASA 1 and 2 patients. The authors suggested that through an increase in tissue partial pressure of oxygen there was improved tissue healing and therefore a reduction in infection rates. As there was no monitoring of cardiac index in the control group. Although we did not recognize any signs of postoperative myocardial infarction in our patients. Pearse et al. [28]. We think the reason for these conflicting results is the selection of patients and surgical interventions.In our study. This is not surprising as the use of inotropes was part of the algorithm for the GDT. multi-center trial with GDT vs. special attention will be necessary in high-risk cardiac patients.8% of patients in the SG received inotropes compared to none in the CG. but not bowel surgery. Again. fit patient receiving low invasive and in particular laparoscopic surgery. These suggestions are supported by our results. A currently published meta-analysis could not identify evidence for an increased risk of treatment-related cardiac complications following the use of inotropes due to GDT [36]. They showed that for aerobically fit patients. Challand et al. what could physicians base the decision to use inotropes on? In an earlier study. We did not measure oxygen demand or the tissue partial pressure of oxygen but our algorithm was aimed at optimizing intravascular volume and CI resulting in the same effect of improved tissue perfusion and oxygenation. Two very recent trials investigated the effects of GDT in colorectal surgery with deviating results. In our study.5]. in particular. . [34] conducted a double-blinded controlled trial with goal-directed vs. pneumonia and urinary tract infections [33]. mostly ASA 1 and 2 patients and also patients undergoing laparoscopic surgery were included. That is why for this trial we chose only to investigate major open abdominal surgery and to exclude laparoscopic procedures and ASA 1 patients. zero fluid balance in open and laparoscopic colorectal surgery showing no differences in length of hospital stay or complications. GDT was associated with no benefit and even had detrimental effects on the readiness for discharge and length of hospital stay. Brandstrup et al. because the study design did not include subgroup-analysis. This supports previous results where GDT was found to be of great benefit especially in patients with bowel surgery [4. but it is important to note that. This is in line with a recent meta-analysis demonstrating that perioperative goal directed therapy resulted in a significantly reduced number of surgical site infections. In these patients we would not expect there to be any great advantages to GDT. and also the number of patients being treated with vasopressors intraoperatively was not significantly different between the two groups. A further sub-analysis revealed that in particular patients undergoing bowel surgery and treated by GDT seemed to suffer significantly less complications. 41. further research needs to be directed at this growing subgroup of surgical patients. infection complications were significantly reduced in the SG.

Detailed analysis of intraoperative hemodynamic parameters suggests that the timing of fluid loading was better in the SG. Further. adding an individualized treatment goal of cardiac index. the CI trending ability seems to be sufficient [12. However. in terms of a stepwise extension of hemodynamic monitoring. therapy is undirected and may be delayed because of the anesthesiologists' fear of fluid overload with its potential harmful consequences.e. we assume that control group care was adequate according to clinical expertise and local standards in the participating institutions. which are all high-volume university centers. if large amounts of blood loss with severe hemodynamic instability are anticipated during the course of surgery. 45. or if the patient is at high risk due to comorbidities. it would have been of interest to have these data for comparison with the study group as well. this study cannot answer the question. if the algorithm proposed here. since arterial pulse contour analysis and the determination of PPV only works reliably in patients without devere arrhythmias and under fully controlled ventilation.and postoperative data suggest that if there is no algorithm. The clinical usefulness in hemodynamically stable patients undergoing major surgery is strengthened by the present data. There are several limitations to this study: Only the patients were blinded to their group allocation. nurses and investigators could not be blinded because of the use of PPV and CI monitoring and the corresponding algorithms. The results support a goal-directed therapy approach in order to reduce complications and therefore patient morbidity. although this technique may not provide optimal precision. i. Furthermore. Finally. we cannot fully eliminate the possibility that the difference in outcomes is not due to benefit in the intervention group but due to poor care in the control group. However. we would recommend additional and more precise monitoring devices for these patients. The intervention in this study. the results of this study are not transferrable to all patients undergoing major abdominal surgery. Conclusions In conclusion this is the first randomized multi-center study on perioperative hemodynamic GDT for patients undergoing major abdominal surgery. the modification of hemodynamic therapy was initialized intraoperatively. We also analyzed the number of patients with complications since this might have been more relevant due to the fact that one patient may develop a large number of complications if they develop multi-organ failure. Since control group care was entirely performed on the discretion of the care-giving anesthesiologist. which was adopted from earlier studies in this field. as for example during major vascular surgery or liver transplant. we decided to omit any additional monitoring in the control group to guarantee that no PPV or CI information could be obtained from the treating anesthesiologist. The rationale was to initiate “earliest goal directed therapy” to maximize the treatment benefit for the whole perioperative course of the patients. Physicians.13.18. is superior to earlier suggested treatment algorithms. This needs to be answered in future trials. This was also the case immediately after arrival at the PACU. . Measurements of PPV and pulse contour CI were taken via a regular radial arterial line although validation studies of similar devices for monitoring CI have shown varying results.38]. These intra. But of course. as the MAP was significantly higher at four time points of measurement (30. Certainly. 120 and 150 minutes). Sample size calculation was based on the reduction of the total number of complications.

CI. Mean arterial pressure. based on radial artery pulse contour analysis leads to a reduction of postoperative complications in patients undergoing intra-abdominal surgery. • The here proposed algorithm-driven hemodynamic optimization induced in some patients the additional application of inotropes. CG. POSSUM. JP has no other conflicts to declare. Control group. CS has no other conflicts to declare. Study group Competing interests This investigator-initiated and investigator-driven study was supported by an unrestricted research grant from PULSION Medical Systems (Munich. Cardiac output. • The net amount of fluid and volume application is not increased by the application of a goal-directed hemodynamic algorithm based on pulse pressure variation. if this application contributed to the reduction in complications. GDT. SG. BB is a board member of PULSION medical systems and received lecture honoraria from Edwars and Deltex. AH has no other conflicts to declare. ZM is a board member of PULSION medical systems and Biotest and receives money for consultancy and lectures from PULSION medical systems.Key messages • The perioperative use of an algorithm for hemodynamic therapy. . SGS is a board member of PULSION medical systems and receives money for consultancy and lectures. Cardiac index. Post anesthesia care unit. AC has no other conflicts to declare. cardiac index and mean arterial pressure. CO. KK has no other conflicts to declare. American society of anesthesiology. PACU. MYK is a board member of PULSION medical systems. JB is a board member of PULSION medical systems. It needs to be clarified in future studies. Germany). MAP. Biotest. Goal-directed hemodynamic therapy. Pulse pressure variation. DAR is a board member of PULSION medical systems and received lecture honoraria from PULSION and Edwards. Abbreviations ASA. and Thermofisher. PPV. Physiological and operative severity score for the enumeration of mortality and morbidity.

acquisition of data. MYK participated in the design of the study. 2. Metnitz P. revised the manuscript critically for important intellectual content and gave final approval of the version to be published. helped to draft the manuscript. Pearse RM. Mayall R. revised the manuscript critically for important intellectual content and gave final approval of the version to be published. revised the manuscript critically for important intellectual content and gave final approval of the version to be published. acquisition of data. AC participated in acquisition of data. Anesthesia 2002. revised the manuscript critically for important intellectual content and gave final approval of the version to be published. AH participated in the acquisition of data. acquisition of data. acquisition of data. revised the manuscript critically for important intellectual content and gave final approval of the version to be published. revised the manuscript critically for important intellectual content and gave final approval of the version to be published. Heckel K. Abdul-Latif MS. Moreno RP. All authors read and approved the final manuscript. Goetz AE. Bauer P. revised the manuscript critically for important intellectual content and gave final approval of the version to be published. JP participated in acquisition of data. ZM participated in the design of the study. BB participated in the design of the study. Vallet B. Pelosi P. 380:1059–1065. 3. 47:845–849. revised the manuscript critically for important intellectual content and gave final approval of the version to be published and supervised the research group. JB participated in the design of the study. Acknowledgement This investigator-initiated and investigator-driven study was supported by an unrestricted research grant from PULSION Medical Systems (Munich. tools and strategies. References 1. drafted the manuscript and gave final approval of the version to be published. revised the manuscript critically for important intellectual content and gave final approval of the version to be published. Reuter DA: Perioperative fluid and volume management: physiological basis. Tackaberry C: Randomised controlled trial investigating the influence of intravenous fluid titration using esophageal Doppler monitoring during bowel surgery. acquisition of data. KK participated in the acquisition of data. Gilligan S.Authors’ contributions CS participated in the acquisition of data. DAR participated in the design of the study. Rhodes A: Mortality after surgery in Europe: a 7 day cohort study. 1:2. . analysis and interpretation of the data. Strunden MS. analysis and interpretation of the data. Spies C. helped to draft the manuscript. Germany) and by institutional support of the participating centers. Ann Intensive Care 2011. Conway DH. Hoeft A. SGS participated in the design of the study. analysis and interpretation of the data. Lancet 2012. Vincent JL. revised the manuscript critically for important intellectual content and gave final approval of the version to be published.

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38. CT = computed tomography. Hüter L. AF = atrial fibrillation. UTI = urinary tract infection. Intensive Care Med 2011. ECG = electrocardiogram. Michard F. WBC = white blood cell count. PPV = pulse pressure variation. Tan A. Additional files Additional_file_1 as DOC Additional file 1 Types and clustering of complications. Additional_file_3 as DOC Additional file 3 Hemodynamic parameters intraoperative. HR = Heart rate. MAP = mean arterial pressure. Additional_file_2 as DOC Additional file 2 Patient recruitment. 37:233–240. Marx G. MAP = mean arterial pressure. Van Nuffelen M. De Backer D. CI = cardiac index. Vincent JL: Arterial pressure-based cardiac output monitoring: a multicenter validation of the third-generation software in septic patients. Junker C. . AMI = acute myocardial infarction. Ching W. CVP = central venous pressure. VF = ventricular fibrillation.

at least 2. CI: Patient individual Value. consider inotropes no CI >2.a no PPV<10 % yes Fluids Determination of optimal CI (at least 2. consider inotropes Reassess every 15 min.5 l/min/m 2 no Inotropes yes no MAP >65 mmHg Figure 1 Vasopressors .5 l/min/m2) Stop if CI decreases.5 l/min/m2 Inotropes yes no MAP >65 mmHg Vasopressors b no PPV <10 % Fluids yes Stop if CI decreases.

160 140 Control group Study group Mean arterial pressure [mmHg] 120 * * 60 90 120 100 80 60 40 20 0 0 30 150 * 180 210 240 270 300 Figure 2 Duration of Surgery [minutes] .

(b) Number of complications 20 40 60 80 0 (a) Number of patients 40 10 20 30 0 in al C ar di ov as cu la r R es pi ra to ry R en al O th er s Figure 3 To To ta l In fe Ab do m * In fe ct io n ta l * * ct io n Ab do m in al C ar di ov as cu la r R es pi ra to ry * R en al O Control group Study group Control group Study group th er s .

30 * Number of patients with complications 25 Control group Study group 20 15 10 5 0 Figure 4 Bowel surgery No bowel surgery .

doc Additional file 2: 1069099288970922_add2. 99K http://ccforum. 37K http://ccforum.doc.com/imedia/1491288156105081/supp3.doc .doc.Additional files provided with this submission: Additional file 1: 1069099288970922_add1.doc.com/imedia/1958861201050815/supp1.doc Additional file 3: 1069099288970922_add3. 39K http://ccforum.com/imedia/5908134391050815/supp2.

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