This article is accompanied by the following Invited Commentary:
Felton T, Columb M. Cardiorespiratory interaction: a novel mechanical approach to treating intraoperative hypotension. Eur J Anaesthesiol 2015; 32:374–375.
Intraoperative hypotension is a common event associated with significant morbidity and mortality.1 Intrathoracic pressure regulation (IPR) devices have been shown to enhance circulation in apnoeic and ventilated normovolaemic and hypovolaemic animals,2–4 and in hypotensive pigs during cardiopulmonary resuscitation.5,6 The reduced airway pressures created by the IPR devices are transmitted immediately to the intrathoracic space, resulting in greater venous return to the heart, increased cardiac output and decreased intracranial pressure.3,4 The IPR device used in this study is inserted into a standard breathing circuit between the patient and the ventilator. After the unimpeded delivery of a positive pressure breath, this IPR device enables an external vacuum source to generate a negative airway pressure during the expiratory phase. Two other types of IPR device are available for use in either spontaneously breathing patients (inspiration through the device creates the negative airway pressure7) or during cardiopulmonary resuscitation (CPR) (chest recoil on the decompression phase creates the negative intrathoracic pressure). With the latter IPR device, results from out-of-hospital cardiac arrest studies have shown increases in cardiac output, blood pressure (BP) and survival.8–10 IPR therapy has also been noted to increase cardiac output in euvolaemic anaesthetised patients undergoing coronary artery bypass graft surgery.11
The objective of the present phase II study was to demonstrate the feasibility of using the IPR device to treat intraoperative hypotension in anaesthetised patients and to evaluate the haemodynamic effects. By increasing BP and pulse pressure (PP), an indirect measure of stroke volume, we hypothesised that the IPR device could be used as a noninvasive treatment for hypotension.
Materials and methods
This prospective evaluation (IRB 0904M63183) was approved by the Institutional Review Board on 11 May 2009 by Research Compliance Supervisor F. Mroczkowski at the University of Minnesota (University of Minnesota, Research Subjects’ Protection Program, Minneapolis, MN 55455, USA) and written informed consent was obtained from all patients.
The IPR study device (CirQLATOR; Advanced Circulatory, Roseville, Minnesota, USA) is a device that is cleared by the United States Food and Drug Administration and is indicated to enhance circulation in states of low blood flow. Specifically, this device was designed for patients who are mechanically ventilated. This phase II pilot study focused on patients undergoing surgery who developed hypotension unrelated to the immediate time period following induction of anaesthesia. Patients meeting the following inclusion criteria were recruited: scheduled for elective surgery at the University of Minnesota Fairview Hospital, aged at least 18 years, elective abdominal or pelvic surgery, normal pulse oximetry on room air and American Society of Anesthesiologists (ASA) physical status I to III. Patients with a history of difficult airway, significant cardiovascular or pulmonary comorbidities including asthma, chronic obstructive pulmonary disease, pneumonia, acute respiratory distress syndrome, pneumothorax or congestive heart failure were excluded. Informed consent was obtained on the day of surgery. Patients requiring regional anaesthesia were not evaluated. A hypotensive event was defined as a more than 20% reduction in SBP from the preinduction value, or any reduction below 90 mmHg, which occurred at least 10 min following induction of anaesthesia. When hypotension occurred, rather than immediately administering intravenous fluids or vasopressor agents, the attending anaesthesiologist made a concerted effort to utilise the IPR device. Each patient served as their own control with haemodynamic parameters compared in the absence and presence of the IPR device.
Upon arrival to the operating room, baseline physiological data were noted and thereafter continued to be recorded every 2 min as part of routine standard ASA monitoring. Once an intraoperative hypotensive episode was confirmed, the IPR device was inserted into the respiratory circuit and activated. The IPR device setup and a representative airway pressure tracing are shown in Fig. 1. The central piped vacuum system served as the vacuum source for the IPR device. The fresh gas flow into the anaesthesia circuit was adjusted to maintain an inflated bellows thus ensuring delivery of a consistent tidal volume in the presence or absence of the IPR device. End-tidal anaesthetic agent concentrations were monitored to ensure they remained constant during IPR use. If the threshold BP was not attained within 6 min, the anaesthesiologist could then use more traditional therapies (e.g. intravenous fluids, blood, blood products, vasopressor, change in anaesthetic regimen) to increase the BP. If the patient suddenly developed severe hypotension, the anaesthesiologist was free to use any additional therapies deemed appropriate at any time. Although the recommended duration of IPR therapy was at least 10 min, the IPR treatment duration could be shorter or longer at the discretion of the attending anaesthesiologist. IPR therapy could be used for multiple hypotensive episodes during the same procedure. BP was measured automatically from an oscillometric cuff around the upper arm. SBP, DBP, PP and heart rate (HR) were recorded. Respiratory parameters including respiratory rate, pulse oximetry (SpO2) and end-tidal carbon dioxide concentration (ETCO2) were also recorded. Patients were mechanically ventilated (volume-controlled mode) with a tidal volume of 8 to 10 ml kg−1 ideal body weight. Positive end-expiratory pressure (PEEP) was not used: the mechanism of action of the IPR device creates a negative intrathoracic pressure of -12 cmH2O during the expiratory phase and is thus incompatible with PEEP. A fractional inspired oxygen (FiO2) of approximately 0.5 (air/oxygen mixture) was used throughout the study.
The primary endpoints included the changes in SBP and PP from immediately before IPR device placement to that at 10 min of IPR use. Additional comparisons included changes in mean arterial pressure (MAP) from immediately before device placement with those values measured at 10 min of IPR therapy, time to highest SBP and PP after IPR placement and the haemodynamic changes 4 min after removal of the IPR device. All continuous data are expressed as mean ± standard deviation (SD). Paired Student's t-test was used to compare the haemodynamic changes pre and post-IPR, and P value less than 0.05 was considered as statistically significant.
Twenty-two patients were enrolled in this phase II study. Seven did not experience hypotensive events leaving 15 patients with 18 hypotensive episodes for treatment with IPR therapy. Patient characteristics, operative and baseline haemodynamic data are summarised in Table 1. All of these hypotensive episodes were treated with IPR therapy for at least 10 min. Figure 2 shows the SBP responses for individual patients. Fourteen episodes were treated solely with IPR therapy and four episodes required additional therapy after 10 min. Significant increases in SBP, PP and MAP are summarised in Table 2 at 10 min of IPR treatment. Additional haemodynamic and respiratory data are also provided in Table 2. Upon removal of the device, there were 13 episodes wherein data were collected and wherein no additional therapy was required. SBP and PP were 101.5 ± 18.4 and 40.4 ± 8.5 mmHg, respectively, at 4 min after cessation of IPR therapy. Pulse oximetry remained unchanged during IPR use when using an average FiO2 of 0.5. There were no peri-operative adverse events or complications observed. There were no signs of decreased oxygen saturation indicative of atelectasis and airway de-recruitment in using IPR during the study.
IPR therapy was insufficient by itself to treat four episodes of intraoperative hypotension that occurred in four patients. One patient was undergoing an exploratory laparotomy for a bowel obstruction and developed significant hypotension 15 min into the surgery and this was treated with a fluid bolus after 12 min of IPR therapy. The second patient underwent a surgical procedure for a uterine tumour and developed significant hypotension at 20 min postinduction; this was treated with phenylephrine and a fluid bolus after 12 min of IPR device use. The third patient undergoing surgery for an ovarian mass experienced two hypotensive episodes; the first occurred 76 min after induction and was treated with IPR therapy only for 18 min, the second episode occurred 108 min after induction and was treated with IPR therapy for 10 min before a fluid bolus was administered. The fourth patient underwent a kidney transplant and developed hypotension 192 min after induction; this was treated with phenylephrine after 18 min of IPR therapy.
Serious intraoperative hypotension can be life-threatening and can develop suddenly and unexpectedly. Although conventional therapies such as volume replacement and vasopressor therapies are often effective, they can be associated with significant adverse effects ranging from volume overload to haemodilution and ischaemia. The purpose of this investigation was to assess the potential clinical value of a new clinical tool to treat intraoperative hypotension by regulating intrathoracic pressure and thereby reducing the need for additional fluids or drugs. A similar physiological concept has been used for over 10 years during CPR to treat profound hypotension associated with cardiac arrest.8,9,12
This phase II study is the first to evaluate the therapeutic benefits of IPR in the setting of intraoperative hypotension. The results demonstrate that IPR can be used rapidly and safely to improve hypotension in anaesthetised patients with low to moderate preoperative risk. The mean SBP over 10 min of IPR use in 12 of 15 patients improved during use of IPR therapy. In one patient with two applications of the device, mean SBP improved during one application but did not improve during the second application. Importantly, MAP significantly improved after 10 min of use as summarised in Table 2 and is generally considered to be a better measure of tissue perfusion than SBP. Although we did not directly measure cardiac output, a significant increase in PP in the presence of a minimum change in HR indirectly suggests augmentation of cardiac output during IPR application. It is noteworthy that the increases in SBP and DBP were relatively rapid and, unlike the response often seen with pharmacological agents, the effect was sustained without overshoot (i.e. similar to a normal physiological response). When the IPR device was removed, these pressures generally remained constant. This suggests that the IPR device helped to reset the cardiovascular stability of the subjects, most likely by increasing and facilitating central venous return and thereby improving circulation and vital organ perfusion. This finding was not analysed for statistical significance.
Not all patients responded satisfactorily with an increase in BP when IPR therapy was used. Supplemental conventional fluid or vasopressor therapy was needed to treat four of 18 hypotensive episodes. This is not surprising, as IPR therapy has limitations and may not be effective for all causes of hypotension. Nonetheless, the ease of use and the potential benefits of IPR therapy were demonstrated in 14 (78%) hypotensive episodes. These results are consistent with our prior experience of IPR devices in hypotensive animal models2,4 and in euvolaemic normotensive anaesthetised patients awaiting coronary bypass surgery.11
This study has several limitations. First, although we assume that the results represent the effect of IPR therapy, it is possible that these may, in part, reflect spontaneous improvements in BP over time. However, previous studies in animal models of shock that included control and intervention study arms have consistently demonstrated conclusive haemodynamic benefits from IPR therapy.2,3 Second, this phase II study focused on true intraoperative hypotension rather than that following induction with general anaesthesia. The mechanism of postanaesthesia-induction hypotension is mainly a combination of loss of sympathetic tone, myocardial depression and reduced venous return, the latter associated with the initiation of positive pressure ventilation. It remains unknown whether IPR therapy will be of benefit in the treatment of this hypotension following induction of general anaesthesia. Third, this study only evaluated short durations of IPR use and, at most, for only up to three hypotensive episodes in a patient. It is not known how many times IPR could be used, nor for what duration, as any IPR benefit might be compromised by a decrease in oxygenation because of the absence of PEEP. Fourth, general anaesthesia was not standardised nor was there a definitive protocol for fluid administration or drug use during a hypotensive episode. Finally, the study was limited to ASA physical status I to III patients undergoing elective abdominal or pelvic surgery requiring general anaesthesia. In this phase II trial, we sought to minimise potential complications related to cardiovascular or pulmonary comorbidities and thus did not enrol patients with known active lung or cardiac disease. We did not observe any deleterious effects on pulse oximetry but, as blood gas analyses were not performed, specific effects on the gas exchange properties could not be fully assessed.
In conclusion, the findings of this small phase II clinical trial to assess the value of IPR therapy in treating intraoperative hypotension suggest that it may be used safely, either alone or as an adjunctive therapy, to improve hypotension in the intraoperative setting. Larger studies that directly assess changes in stroke volume or cardiac output and potential adverse effects will be helpful in defining the clinical utility of IPR therapy for the treatment of intraoperative hypotension.
Acknowledgements relating to this article
Assistance with the study: Chandra J. Castro (Department of Anaesthesiology, University of Minnesota, Minneapolis, Minnesota, USA); Amanda M. Murray (Department of Anaesthesiology, University of Minnesota, Minneapolis, Minnesota, USA).
Financial support and sponsorship: an unrestricted research grant was made to the Anesthesiology Department by the manufacturer of the IPR device used in the study, and the devices were also provided free of charge.
Conflict of interest: none.
Presentation: preliminary data from this study were presented as a poster presentation at the American Society of Anesthesiologists annual meeting, 16 to 20 October 2010, San Diego, California, USA.
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