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versión impresa ISSN 0103-507X
Rev. bras. ter. intensiva vol.24 no.2 São Paulo abr./jun. 2012
ORIGINAL ARTICLES - BASIC RESEARCH
Acute hemodynamic, respiratory and metabolic alterations after blood contact with a volume priming and extracorporeal life support circuit: an experimental study
Marcelo Park; Eduardo Leite Vieira Costa; Alexandre Toledo Maciel; Adriana Sayuri Hirota; Edzangela Vasconcelos; Luciano Cesar Pontes Azevedo
On behalf of Hospital das Clínicas de São Paulo and Hospital Sírio Libanês ECMO group*
OBJECTIVE: To investigate
the hemodynamic, respiratory and metabolic impact of blood contact with
a priming volume and extracorporeal membrane oxygenation circuit, before the
initiation of oxygenation and ventilation
METHODS: Five animals were instrumented and submitted to extracorporeal membrane oxygenation. Data were collected at the baseline and 30 minutes after starting extracorporeal circulation, without membrane ventilatory (sweeper) flow.
RESULTS: After starting extracorporeal membrane oxygenation, there was a non-significant elevation in pulmonary vascular resistance from 235 (178,303) to 379 (353,508) dyn.seg.(cm5)-1 (P=0.065), associated with an elevation in the alveolar arterial oxygen gradient from 235 (178,303) to 379 (353,508) mmHg (P=0.063). We also observed a reduction in the left ventricle stroke work from 102 (94,105) to 78 (71,87) (mL.mmHg)/beat (P=0.064), in addition to a reduction in cardiac output from 7.2 (6.8,7.6) to 5.9 (5.8,6.3) L/min (P=0.188). The right ventricle stroke work was counterbalanced between the pulmonary vascular resistance increment and the cardiac output reduction, maintaining a similar value.
CONCLUSIONS: We presented an experimental model that is feasible and safe. Blood contact with the priming volume and extracorporeal membrane oxygenation circuit resulted in non-significant systemic or metabolic changes.
Keywords: Acute respiratory distress syndrome; Respiration, artificial; Extracorporeal membrane oxygenation; Multiple organ failure; Swine
Extracorporeal membrane oxygenation (ECMO) has been used to support patients with severe respiratory and/or cardiovascular failure.(1) Despite increasing clinical experience and success,(2-5) there are currently few reports in the literature about the physiology and about acute patients' experienced with ECMO use.(6)
In animal studies, the use of polypropylene ECMO is associated with an acute elevation of plasmatic interleukins and with intestinal and pulmonary edema.(7) Accordingly, gut barrier dysfunction associated with polypropylene ECMO use can be an important contributor to ECMO-related systemic inflammation.(8) In human beings, respiratory support using polymethylpentene ECMO membranes is also associated with early, new, radiographic pulmonary infiltrates, a phenomenon known as white-out.(9) The development of bioactive and biopassive coated extracorporeal circuits reduced inflammatory and pro-coagulant pathway activation in a simulated model.(10)
Routine priming using calcium salts can prevent severe hypocalcemia in neonates;(11) however, the effects of priming with normal saline have not been characterized. Thus, the aim of this study was to describe the acute hemodynamic, respiratory and metabolic effects of blood-extracorporeal circuit contact and priming with normal saline in an animal model.
This study received approval from the Institutional Animal Research Ethics Committee and was performed according to National Institutes of Health guidelines for the use of experimental animals. The instrumentation and surgical preparation were performed as previously described.(12-14)
Instrumentation and surgical preparation
The room temperature was set at 24ºC. Five domestic female Agroceres pigs (80±3 kg) were anesthetized with thionembutal (10 mg/kg, Tiopental, Abbott, Brazil) and pancuronium bromide (0.1 mg/kg, Pavulon, AKZO Nobel, Brazil) and were connected to a mechanical ventilator (Evita XL Dräger, Dräger, Luebeck, Germany) with the following parameters: tidal volume 8 mL/kg; end-expiratory pressure 5 cm H2O; FIO2 initially set at 100% and subsequently adjusted to maintain arterial saturation between 94% and 96%; and respiratory rate titrated to maintain PaCO2 between 35 and 45 mm Hg or end-tidal CO2 (NICO, Dixtal Biomedica Ind. Com, Sao Paulo, Brazil) between 30 and 40 mm Hg. The electrocardiogram, heart rate, oxygen saturation, and pressures of the animals were monitored with a multiparametric monitor (Infinity Delta XL, Dräger, Luebeck, Germany). Anesthesia was maintained during the study with midazolam (1- 5 mg.kg-1.h-1) and fentanyl (5-10 mcg.kg-1.h-1, Fentanyl; Janssen-Cilag, Brazil), and muscular relaxation was maintained with pancuronium bromide (0.2 mg.kg-1.h-1). The adequate depth of anesthesia during the surgical period was evaluated with the maintenance of physiological variables (heart rate and arterial pressure) and the absence of reflexes (corneal and hind limb flexion response), as well as unresponsiveness to stimuli during manipulation. Supplementary boluses of 3 - 5 mcg/kg fentanyl and 0.1 0.5 mg/kg midazolam were administered as necessary.
The left external jugular vein was cannulated (guided by ultrasonography) to introduce a pulmonary artery catheter, and the right external jugular vein was cannulated to introduce a 25-cm ECMO devolution cannula (Edwards Lifesciences, Irvine, CA, USA). The right femoral vein was punctured for the insertion of a 55-cm ECMO drainage cannula (Edwards Lifesciences, Irvine, CA, USA), which was positioned close to the right atrium with the aid of trans-hepatic ultrasonographic visualization. Only the guidewires were kept in place after the first baseline measurements during the stabilization period; the guidewires were then replaced by the cannulas. After the insertion of the guidewires, an infusion of 1000 IU per hour of heparin was started. A central venous catheter and an invasive arterial blood pressure catheter were placed in the left femoral vein and artery, respectively.
Through a midline laparotomy, a cistostomy was performed, and a bladder catheter was inserted. During the surgical interventions, 15 mL.kg-1.h-1 of lactated Ringer's was continuously infused, and boluses of 250 mL were administered to maintain a systemic mean arterial blood pressure (ABPm) of 65 mm Hg or greater, a central venous pressure (CVP) of 8 mm Hg or greater, and SvO2 greater than 65% until the end of instrumentation.
Stabilization and support of the animals
After the end of the instrumentation, the animals were allowed to stabilize for 1 h. At the beginning of the stabilization period, a continuous infusion of 3 mL.kg-1.h-1 of lactated Ringer's was started and maintained throughout the entire experiment.
When the animals became hypotensive (ABPm<65 mm Hg), a bolus of 500 mL of lactated Ringer's was infused. If the ABPm failed to rise above 65 mmHg after the bolus, an infusion of norepinephrine 0.1 mcg.kg-1.min-1 (Norepine, Opem Pharmaceuticals, São Paulo, Brazil) was started and titrated to an ABPm≥65 and <80 mmHg.
ECMO priming, starting, and maintenance
The ECMO system (Permanent life support system - PLS, Jostra Quadrox D, Maquet Cardiopulmonary, Hirrlingen, Germany) was primed with a 37ºC normal saline solution and connected to a centrifugal pump (Rotaflow, Jostra, Maquet Cardiopulmonary, Hirrlingen, Germany). With the circuit filled, 1000 IU of heparin were injected in the circulating fluid.
The PLS uses a polymethylpentene membrane; the tubes are coated with a bioactive and biopassive system (Bioline, Maquet Cardiopulmonary, Hirrlingen, Germany).(10) Two Luer locks were connected, respectively, to the pre- and post-membrane ports, to allow for the measurement of pressures and for the collection of blood samples. Pressure lines were connected to the ports in the drainage tube (before the centrifugal pump), before and after the ECMO membrane; pressure measurements were performed in real time with a multiparametric monitor (Dx 2020, Dixtal Biomedical Ind. Com, Sao Paulo, Brazil).
After the baseline measurements, the extracorporeal circulation was initiated with blood flow of 1.5 L/minute and with the gas (sweeper) flow turned off. After a stabilization period of 30 min, a second baseline was measured with blood, but no gas flow, through the membrane, i.e., without gas exchange, with the aim of assessing the isolated effects of blood contact with the ECMO circuit.
The following data were collected: heart rate (HR); mean arterial blood pressure (ABPm); central venous pressure (CVP); mean pulmonary artery pressure (PAPm); pulmonary artery occluded pressure (PAOP); cardiac output (CO); core temperature; peripheral oxygen saturation; end-tidal CO2 (EtCO2) and mixed venous oxygen saturation (SvO2); PEEP; FiO2; auto-PEEP measured with 4 seconds of expiratory pause; plateau pressure with 2 seconds of static inspiratory pause; and peak pressure. Blood samples from the pulmonary and femoral arteries were collected and analyzed in a standard ABL 600 radiometer (Radiometer, Copenhagen, Denmark). The samples from the femoral artery were used for the biochemical analysis.
The calculations were performed using standard formulas as follows.(13-16) Static respiratory compliance (mL/mmHg): Cst = tidal volume/(plateau pressure PEEP); dynamic respiratory compliance (mL/mmHg):Cdyn = tidal volume/(peak pressure PEEP); airway resistance (mmHg.L-1.s-1): Cst = (peak pressure plateau pressure)/inspiratory airway flow; alveolar arterial oxygen gradient (mmHg): D (A a) O2 = [FiO2 • 643 (PaCO2 / 0.8) PaO2]; systemic vascular resistance (dyn.seg.cm-5): SVR = (ABPm CVP) • 80/ cardiac output; pulmonary vascular resistance (dyn.seg.cm-5): PVR = (PAPm PAOP) • 80/ cardiac output; right ventricle stroke work (mL.mmHg/beat): RVSW = (PAPm PAOP) • stroke volume 0.136; left ventricle stroke work (mL.mmHg/beat): LVSW = (ABPm CVP) • stroke volume 0.136; standard base excess (mEq/L): SBE = 0.9287 • (HCO3¯ 24.4 + 14.83 • (pH 7.4)).
The data were predominantly non-parametrical as assessed using a Shapiro-Wilk goodness-of-fit model. Consequently, the data are shown as medians and 25th and 75th percentiles. Paired data were analyzed with Wilcoxon's test. The R free source statistical package and comprehensive-R archive network (CRAN)-specific libraries were used to build the graphics and to perform all of the statistical analyses.(17)
Table 1 and Figure 1 show the hemodynamic, respiratory and metabolic consequences of priming and blood-ECMO membrane contact. Despite the absence of statistical significance, it is interesting to note the elevation of mean pulmonary artery blood pressure, resulting in higher pulmonary vascular resistance, in addition to lower cardiac output and a reduced left ventricle stroke work index. It is also interesting to note the trend toward elevation of the alveolo-arterial oxygen gradient. There were trends toward the reduction of the core temperature and chloride elevation.
In this study, there were no significant differences in the measured respiratory, hemodynamic and metabolic variables before or after blood contact with an ECMO circuit and fluid priming.
The core temperature decrease and chloride elevation could be explained by the system's normal saline priming, not necessarily reflecting the contact of blood with the ECMO circuit. We cannot exclude the possibility of chloride elevation due to systemic inflammation, as described with endotoxemia.(18) One could expect more metabolic alterations due to the sudden increase in intravascular distribution volume; however, in this model using large animals, those expected alterations did not occur.
The remaining alterations were likely related directly or indirectly to blood contact with the membrane. The increase in the alveolar-arterial oxygen gradient and the increase in the pulmonary vascular resistance were in line with the pulmonary injury and systemic inflammation in animals supported by a polypropylene-based ECMO device,(7) added to the pulmonary white-out of patients supported by polymethylpentene-based ECMO systems.(9) The increase in the pulmonary vascular resistance could per se explain the reductions in cardiac output and in left ventricle stroke work. The right ventricle stroke work did not increase, most likely due to the counterbalance between the higher pulmonary arterial pressure and the reduced cardiac output. Although more biocompatible than polypropylene-based membranes, contact of the blood with polymethylpentene-based ECMO circuits still induces changes noticeable at the bedside with potential clinical importance.(9) In other words, the contact of blood with the priming volume and the ECMO circuit could be responsible for left ventricle dysfunction, likely via an inflammatory pathway,(19) causing pulmonary hypertension and the elevation of the alveolar-arterial gradient of oxygen. Another point to consider is the temperature decrease, which could be at least partially responsible for the alterations measured.
Weighting our findings, the non-significant alterations in respiratory physiology and hemodynamics, the advantage of using protective or ultra-protective mechanical ventilation will likely be greater than the lung injury in this
The strength of this study is its first characterization of immediate systemic alterations due to blood contact with the priming volume and the circuit in the ECMO at the beginning, without the influence of oxygenation. However, the study has several limitations: 1) the small number of animals rendered the power of the study poor and was likely responsible for the non-significant findings; and 2) the absence of measurements of inflammatory markers precluded an adequate conclusion correlating the study findings with a systemic inflammatory process.
In this study, the safety and feasibility of the model were demonstrated. Given the low number of animals studied, blood contact with the priming volume and ECMO circuit resulted in non-significant systemic and metabolic alterations.
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Corresponding author: Submitted on March 30, 2012 Conflicts of interest: The authors
received a donation of PLS systems from Maquet Cardiopulmonary from Brazil, to
conduct an experimental research study and for patient support. This study was conducted at the Instituto de Ensino e Educação
do Hospital Sírio Libanês - São Paulo (SP), Brazil.
Rua Francisco Preto, 46
Zip Code: 05623-010 - São Paulo (SP), Brazil
Accepted on June 15, 2012
* Participants in the ECMO group:
Marcelo Park, MD
Luciano Cesar Pontes Azevedo, MD, PhD
Eduardo Leite Vieira Costa, MD, PhD
Pedro Mendes, MD
Alexandre Toledo Maciel, MD
Leandro Utino Taniguchi, MD, PhD
Fernanda Maria Queiroz Silva, MD
André Luiz de Oliveira Martins, MD
Edzangela Vasconcelos Santos Barbosa, RN
Raquel Oliveira Nardi, RN
Michelle de Nardi Ignácio, RN
Cláudio Cerqueira Machtans, RN
Wellington Alves Neves, RN
Adriana Sayuri Hirota, RT
Marcelo Brito Passos Amato, MD, PhD
Guilherme de Paula Pinto Schettino, MD, PhD
Carlos Roberto Ribeiro Carvalho, MD, PhD
Submitted on March 30, 2012
Conflicts of interest: The authors received a donation of PLS systems from Maquet Cardiopulmonary from Brazil, to conduct an experimental research study and for patient support.
This study was conducted at the Instituto de Ensino e Educação
do Hospital Sírio Libanês - São Paulo (SP), Brazil.