Economic impact of therapies on perioperative hemodynamic optimization in surgical patients from the perspective of developing country: Economic study and Meta-analysis

Background: Health resources are limited and need to be rationally distributed. Studies suggest that hemodynamic optimization therapy can reduce length of hospital stay, complications and costs. However, Brazilian data are scarce. Therefore, the objective of this analysis was to evaluate whether the improvement demonstrated by hemodynamic optimization therapy in surgical patients could result in lower costs from the perspective of the Brazilian public unified health s ystem (SUS). Method: A meta-analysis was performed comparing surgical patients who underwent hemodynamic optimization therapy (intervention) with patients submitted to standard therapy (control) in terms of complications and hospital costs. The cost-effectiveness analysis evaluated the clinical and financial benefits of hemodynamic optimization protocols for surgical patients. The analysis considered the clinical outcomes of randomized studies published in the last 20 years that involved surgeries and hemodynamic optimization therapy. Indirect costs were not included in the analysis. Results: A total of 21 clinical trials with a total of 4872 surgical patients were selected. Comparison of the intervention and control groups showed lower rates of infectious (RR=0.66; 95% CI=0.58-0.74), renal (RR=0.68; 95% CI=0.54-0.87), and cardiovascular complications (RR=0.87; 95% CI=0.76-0.99) and a tendency toward lower rates of respiratory complications (RR=0.82; 95% CI=0.67-1.02). There was no difference in mortality (RR=1.02; 95% CI=0.80-1.3) between groups. In the analysis of total costs, the intervention group showed a cost reduction of R$396,024.83 for every 1000 patients treated compared to the control group. The patients in the intervention group showed greater effectiveness, with 1.0 fewer day in the ICU and hospital. In addition, there were 333 fewer patients with complications, with a consequent reduction of R$1,630,341.47 for every 1000 patients treated. Conclusions: Hemodynamic optimization therapy is cost-effective and would increase efficiency and decrease the burden of the Brazilian public health system. catheterization, transpulmonary thermodilution, echocardiography, transesophageal Doppler echocardiography, pulse contour analysis, partial carbon dioxide rebreathing bioimpedance.

and a tendency toward lower rates of respiratory complications (RR=0.82; 95% CI=0.67-1.02). There was no difference in mortality (RR=1.02; 95% CI=0.80-1.3) between groups. In the analysis of total costs, the intervention group showed a cost reduction of R$396,024.83 for every 1000 patients treated compared to the control group. The patients in the intervention group showed greater effectiveness, with 1.0 fewer day in the ICU and hospital. In addition, there were 333 fewer patients with complications, with a consequent reduction of R$1,630,341.47 for every 1000 patients treated.
Conclusions: Hemodynamic optimization therapy is cost-effective and would increase efficiency and decrease the burden of the Brazilian public health system.

Background
Millions of major surgeries are performed every year worldwide [1]. The mortality and morbidity rates of high-risk surgeries vary among countries but are considered high, making them a global problem [2][3][4]. In Brazil, in 2008, the mortality rate of patients admitted to intensive care units after major surgeries was 15%; after 90 days, it reached 20.3%. The main postoperative complication found in Brazil was sepsis (24.7%), and the main cause of death was multiple organ dysfunction [5].
Postoperative complications in high-risk patients undergoing major surgery are associated with low cardiorespiratory reserve and the inability to maintain adequate oxygen delivery (O2) during surgical trauma to meet the increased metabolic demand [6][7][8]. As a consequence, there is an imbalance in the ratio of oxygen delivery to oxygen consumption, leading to hypoperfusion, multiple organ dysfunction and severe infections, which are important causes of postoperative mortality [4].
Perioperative hemodynamic optimization therapy (PHOT) aims to adjust cardiac function to meet the increased demand during the perioperative period, thus avoiding hypovolemia or hypervolemia and, ultimately, tissue hypoperfusion and postoperative complications. This requires adequate hemodynamic monitoring to guide the early treatment of each patient, allowing for earlier identification of the need for fluid optimization, blood transfusion, and vasoactive drugs.
Studies and meta-analyses have shown that PHOT has a significant impact on the outcomes of highrisk patients undergoing major surgery, potentially decreasing morbidity and mortality, length of ICU stay, and length of hospital stay [9][10][11]. However, the risk-benefit ratio of this type of monitoring has been questioned because it is invasive and carries risks [12]. Monitoring techniques include pulmonary artery catheterization, transpulmonary thermodilution, echocardiography, transesophageal Doppler echocardiography, pulse contour analysis, partial carbon dioxide rebreathing and bioimpedance.
Cost-effectiveness is represented by a ratio between monetary cost, usually expressed in a national currency, in the numerator and a measure of health gain in the denominator. The poor adherence to PHOT in clinical practice combined with the need to improve the effectiveness of care for surgical patients in the face of increasing demand points to the urgent need for cost-effectiveness assessments that encourage the use of PHOT in this area, particularly in resource-limited settings.
Health resources are increasingly limited, and a lack of knowledge about a method is a barrier to the implementation of new therapies with proven effectiveness that could not only save lives but also lead to a reduction in resource use. Our hypothesis is that these interventions, due to their significant impact on the length of hospital stay and complications, would be cost-effective for the public health system.
This study aimed to evaluate whether the use of PHOT is cost-effective for patients undergoing major surgery from the perspective of the Brazilian Unified Health System (SUS) by evaluating the impact of a reduction in length of hospital stay, complication rates and mortality on hospital costs.

Materials And Methods
A systematic review of the clinical trials indexed in CENTRAL (PubMed), MEDLINE (OvidSP) and EMBASE (OvidSP) between 2001 and 2018 was performed. The search used the following keywords, which were expected to be present in the title and/or abstracts: "randomized studies" and "surgeries", and/or "perioperative", and/or "high-risk", and/or "complications", and/or "intraoperative" and/or "postoperative", and/or "cardiac output", and/or "cardiac index", and/or "hemodynamic monitoring", and/or "hemodynamic optimization therapy", and/or "hemodynamic intervention", and/or "costeffectiveness", and/or "mortality". Methods identical to those recommended by the Cochrane systematic review of randomized controlled trials on increased blood flow to the organs, with explicitly defined goals and results after surgery, were used.
Only studies published in the English language were included. Two independent researchers identified the titles and abstracts of the potentially eligible studies. Disagreements between the investigators were resolved by consensus. Two other researchers extracted the following data from the full texts of potentially eligible studies: study design, patient population, interventions and outcomes. Similar to the approach used for the selection of texts, any disagreements between researchers regarding the data extraction were resolved by consensus. Each included study was assessed independently by the first and second reviewer for risk of bias in random sequencing generation, allocation concealment, blinding of participants and personnel, blinding of outcomes assessment, incomplete outcome data, selective reporting, and other sources of bias using the Cochrane Risk of Bias Tool. [13] In the absence of appropriate published data, at least one attempt was made to contact the authors of eligible studies to obtain necessary data. The analysis was performed with the best available information when there was no response.
The following information and outcomes were recorded: number of patients with respiratory complications (i.e., the need for respiratory support for more than 24 hours after surgery, hypoxemia, acute changes in lung mechanics), cardiovascular complications (need for hemodynamic support, such as the use of inotropes and vasopressors during the postoperative period), renal complications (oliguria, unexpected increase in creatinine and need for dialysis) and infectious complications (infections that occurred during the postoperative period) based on the records of each study.
Mortality was assessed throughout the longer follow-up period (primary outcome) or was examined as in-hospital mortality. Many studies have reported complications as the number of complications rather than number of patients with complications, but we only reported the last unit in the analysis, which was the number of complications per patient.
To calculate the costs of these complications, only the length of ICU stay was considered.
The inclusion criteria of the selected studies were as follows: 1) studies in adult patients (18 years or older); 2) studies with patients undergoing hemodynamic optimization therapy with some type of cardiac output monitor; 3) studies that related the costs of hemodynamic optimization therapy and its outcomes, such as the reduction of mortality or morbidity rates or the reduction of length of hospital or ICU stay; 4) interventional studies comparing the use of invasive or minimally invasive monitoring with the standard strategy for hemodynamic optimization to alter clinical outcomes. The intervention should meet the following criteria: Perioperative period: The administration of fluids with or without inotropes/vasoactive drugs to increase blood flow (standard therapy group) was compared with goals measured explicitly with invasive or minimally invasive hemodynamic monitoring (intervention group). The perioperative period started at the beginning of surgery and lasted up to 24 hours after surgery. Explicit goals were defined for the cardiac index, oxygen delivery (DO 2 ), oxygen consumption, systolic volume, mixed or central venous oxygen saturation, oxygen extraction, or serum lactate.
The exclusion criteria were as follows: 1) animal studies; 2) studies published prior to 2001; 3) observational studies that did not use clinical intervention to change outcomes or case reports; 4) studies involving critically ill patients prior to intervention or with established sepsis who therefore with a higher probability of unfavorable outcomes and death regardless of intervention.

Cost assessment
For the cost-effectiveness analysis, the costs were separated into 10 categories and two periods: the intraoperative period (monitoring and the costs of fluid infusion, inotropes or vasopressors and blood transfusions) and the postoperative period in the ICU, which was maintained at fixed daily rates regardless of disease, clinical exam and procedures depending on postoperative complications, laboratory diagnosis, use of antimicrobial and other agents (cardiac support, renal support, physical therapy and imaging). To avoid confounding factors, the costs of the surgical procedure (considering that the surgeries would have the same magnitude), postoperative analgesia and preoperative state were excluded from the final sum, as were costs related to the hospital infrastructure (electricity, safety system, etc.).
The overhead costs were estimated from a social perspective, i.e., regardless of who will bear the cost. However, the unit costs of health resources and services were obtained from the national databases of the Brazilian public health system (SUS), and therefore, the direct costs represent the costs borne by the payer [14][15][16][17][18][19].
The incremental cost effectiveness analysis was based on the difference in costs divided by the difference in survival days in each group.

Statistical analysis
The analyses were performed in Review Manager (RevMan 5.2.8) using fixed effects models with random effects models for comparison. We applied the intention-to-treat method for all analyses.
Treatment effects were reported as relative risk (RR) and confidence intervals (95% CI) for clinical variables or as differences in weighted averages (SD) or medians for the length of ICU and hospital stays. Empty cells, the result of studies in which no event was observed in one or both arms, were corrected by adding a fixed value (0.5) to all cells with an initial value of zero. The chi-square test was used to assess whether the differences observed in the results were due to chance. A large chi-square (I 2 statistic) provided evidence of heterogeneity of the intervention effects (indicating that the estimated effect was beyond chance).

Results
Initially, 52 potential articles were identified. After the inclusion and exclusion criteria were applied, 21 articles remained. (Fig. 1) Of the selected studies, 21 used techniques for measuring cardiac output; these studies had a total of 4,872 patients at high surgical risk. (Table 1) Table 1 Selected studies and the technology used for hemodynamic monitoring.
Author-year (ref) Objective Technology Bonazzi et al., 2002 [33] Evaluation of the impact of hemodynamic optimization using a pulmonary artery catheter on the outcome of patients undergoing vascular surgery. The mortality rate in the intervention group was 2.6% (125); in the control group, it was 2.5%. (122) There were no statistically significant differences in mortality rate. (Fig. 3) The rates of infectious complications (RR = 0.66, 95% CI = 0.58-0.74), renal complications (RR = 0.68, 95% CI = 0.54-0.87) and cardiovascular complications after surgery (RR = 0.87, 95% CI = 0.76-0.99) were significantly higher in the control group. Regarding respiratory complications, there was no significant difference in the random effect analysis, but the fixed effect analysis yielded statistically significant differences (RR = 0.81; 95% CI = 0.66-0.98). (Fig. 4) In the comparison between groups, the patients in the intervention group had shorter lengths of hospital and ICU stay. (Table 2)   Table 2 Comparison of the variables analyzed in determining the costs of the intervention and standard therapy groups.  Total -intervention --R$18448.68 * One-time-use or disposable devices: catheters and probes are acquired by the hospital in certain quantities, and the debt is borrowed by the hospital. The amount was extracted from the findings of the studies (Table 2) and extrapolated to represent the costs of 1 patient from a Brazilian cost perspective.

Variables
The intervention group was monitored hemodynamically during the intraoperative period and was managed according to the data measured. The control group did not undergo hemodynamic monitoring and was treated according to the standard procedure.
Regarding complications in terms of only the length of ICU stay, those who received standard therapy showed higher costs when they developed infectious, renal, cardiovascular and respiratory complications. (Fig. 4) Based on these calculations, when estimating costs for the two types of treatment per 1000 patients, the highest costs were observed for the standard treatment in the presence of complications. On the other hand, the benefits were not sustained for patients without complications or those who do not survive because the costs are higher for patients who are treated with goal-directed therapy. (Fig. 5) The cost and final effectiveness of the intervention group (optimization therapy) were lower than those of the control group (conventional therapy). Although there was no significant difference in mortality rates, the cost of patients in the intervention group based on 1,000 treated patients was R$396,024.83 less than that of patients in the standard therapy group (incremental). In addition, the intervention group showed a reduction of R$1,630,341.47 per 1000 patients with complications.  high-cost surgery [28].
Although the results of economic health simulations continue to suggest that perioperative hemodynamic therapy may be economical and, therefore, cost effective, these findings are sensitive to the size of the treatment effect [26,27]. Curiously, the economic evaluations of early hemodynamic therapy in patients with severe sepsis also indicate that treatment can be costeffective [29,30]. However, these analyses are based on the assumption of a strong treatment effect, while the results of recent randomized clinical trials suggest that such protocols have little or no clinical benefit in patients with severe sepsis [31].
Thus, while the findings of the current study are consistent with those of previous analyses, definitive evidence provided by a large clinical effectiveness trial is necessary to confirm the economic impact of perioperative hemodynamic cardiac output optimization therapy. However, we emphasize that the findings are important because they show that perioperative hemodynamic intervention represents an excellent expenditure of public money from the SUS perspective.
However, this study has some limitations that we must discuss, such as the fact that the costeffectiveness analysis was based on data from clinical trials with extrapolated results, despite the use of appropriate methods and long-term survival data. The cost of uncertainty in decision making was calculated along with traditional cost-effectiveness results. Cost data and results were collected only during ICU stays, and the cost-benefit analysis may involve other assumptions that could not be extrapolated with these data. Some follow-up data were missing and were resolved with an approximation by multiple imputation [32]. Furthermore, although economic health data were prospectively included in the dataset, the calculations were based on clinical results. These results should be interpreted considering that most tests are designed to detect differences in clinical effectiveness rather than cost-effectiveness. The costs of health care are more variable than the clinical results, and economic evaluations may therefore lack statistical power. The primary objective of economic evaluation is not to test hypotheses but rather to estimate incremental measures of costeffectiveness and to provide an adequate representation of the uncertainty around these estimates.
Above all, these findings will inform a new clinical policy regarding priorities for future research.