Did Ündar and Associates Really Make Those Comments on the Issue of Pulsatile Versus Nonpulsatile Flow? Absolutely Not.

The Authors Reply: One should not confuse cardiopulmonary bypass during cardiovascular surgery and left heart bypass for mechanical assist circulation in considering the “pulsatile and nonpulsatile” problem. We greatly appreciate the interest and comments of Dr. Ündar, though there are still some differences between his opinions and ours. We hope to clear up some misunderstanding and point out some important points for discussing “pulsatile and nonpulsatile” problems. In discussing the “physiologic effects” of pulsatile and nonpulsatile circulation, many ASAIO Journal readers agree that the definition of pulsatility is one of the most important points. Shepard’s energy equivalent pressure (EEP) form is a possible standard parameter. 1 However, what we would like to make clear is that it is quite an important, as well as accurate definition of pulsatility to distinguish whether the experimental design is for cardiopulmonary bypass during cardiovascular surgery or for left heart bypass as a means of mechanical circulatory assistance for a failed heart. There are many reports regarding the physiologic effects of short-term pulsatile and nonpulsatile cardiopulmonary bypass during cardiovascular surgery, however, those concerning the physiologic effects of long-term pulsatile or nonpulsatile left heart bypass are rare. Our series of studies are intended to clarify the physiological effects of long-term pulsatile and nonpulsatile left heart bypass for the management of patients under prolonged support with nonpulsatile circulatory assist devices. During cardiopulmonary bypass, patients are under anesthesia and/or hypothermic conditions, which likely have an effect on physiologic function, and the duration is typically in the order of hours. Furthermore, in most cases the heart is either fibrillated or rested, thus blood flow in patients maintained by a nonpulsatile blood pump can be kept at almost zero pulse pressure flow. Moreover, the pulmonary circulation is commonly bypassed. In contrast, patients receiving a left heart bypass are in most cases not under anesthesia and/or hypothermic conditions, and the duration of bypass is often in the order of days or months. In most of these cases, heart beating exists, thus blood flow of patients maintained by the nonpulsatile blood pump is kept under reduced pulse pressure flow. Further, the pulmonary circulation is not bypassed. Owing to these differences, readers should not confuse the two experimental settings. In our last letter we made the following comment, “Dr. Ündar and associates pointed out that conflicting data in the literature concerning pulsatile and nonpulsatile circulation is due to the definition of pulsatility. We agree that one of the important causes is a poor definition of pulsatility. However they should be aware that there are also some other important factors”. 2 To which Dr. Ündar replied, “This statement implies that we did not discuss any other factors in this particular publication. In contrast, we clearly stated four reasons. . .” We believe that this is a misunderstanding. We did not assert that Dr. Ündar and associates did not discuss any factors other than the definition of pulsatility. We respect their detailed study, and did not intend to include any discussion concerning Dr. Ündar and associates’ manuscript published in Artificial Organs in 1999. 3 If Dr. Ündar and other ASAIO Journal readers read our previous letter carefully, 2 we believe that our statement; “some other important factors,” can be understood to concern the experimental model and whether it is for cardiopulmonary bypass or left heart bypass, as well as whether the experimental setting is an acute study with surgical intervention and anesthesia or a chronic one without them. Concerning the definition of pulsatile and nonpulsatile circulation, there is also a misconception. In our last letter, 2 we did not take out a sentence from Dr. Ündar and associates’ manuscript entitled “Defining Pulsatile Perfusion: Quantification in Term of Energy Equivalent Pressure.”3 We did not make that statement at all. We simply responded to the statement of Dr. Ündar and associates in the last letter which said, “Because the pulse pressure was 17.4 ± 6.7 mm Hg during nonpulsatile perfusion, the investigators in fact compared two forms of pulsatile flow, not pulsatile versus nonpulsatile flow.”4 What was the reason for Dr. Ündar’s conclusion and his definition of pulsatile flow and nonpulsatile flow in this statement? We understand that their comment “the pulse pressure of 17 mm Hg is not nonpulsatile flow, but pulsatile flow” is based on our pulse pressure value. They also noted in a letter to the report of G. K. Jett 5 that a pulse pressure between 15 and 20 mm Hg during chronic circulatory support with a nonpulsatile left or right ventricular assist device is not nonpulsatile flow, but rather pulsatile flow. 6 Since no other reasons were given, except for the value of pulse pressure, we consider that they made this comment on the basis of a conventional borderline of 15 mm Hg (we apologize to Dr. Ündar if this was our misunderstanding), although we understand that 15 mm Hg is not the criteria advocated by Dr. Ündar and associates. We consider their judgment itself to be a proper one, except for its uncertain basis. We intended to state that the comments concerning their judgment of pulsatile flow or nonpulsatile flow in prolonged left heart support would make no sense. During a left heart bypass with nonpulsatile (continuous flow) blood pumps, the effects of reduced pulse pressure are important. Accordingly, we stated, “Researchers should not confuse a temporary cardiopulmonary bypass with cardiac surgery or a left heart bypass in regards to mechanical circulatory support when discussing the problems of pulsatility. In this study, pulse pressure was reduced significantly to approximately 17 mm Hg, which we considered to be a clinically attainable level in patients undergoing nonpulsatile left heart bypass.” Pulse pressure is still the most popular and widely understandable parameter used when performing left heart bypass with continuous flow blood pumps, in both basic research and clinical medicine, although we understand that it is an incomplete parameter when discussing these problems. In our original report, 7 we investigated the effect of left heart bypass with a nonpulsatile blood pump on hormonal circadian rhythm. Surgical and/or anesthetic stress is quite influential in hormonal circadian rhythm. Accordingly, it is necessary to exclude such factors as much as possible. In this study, to evaluate the effect of prolonged nonpulsatile left heart bypass without surgical stress, anesthesia, or the influence of postoperative derangement, we did not perform a physiologic evaluation until a 2 week postoperative period had passed. After that time, the pulsatile ventricular assist device was switched to a centrifugal pump instantly, without anesthesia or surgical intervention, to perform our assessment. Of course, we were able to investigate this problem using two types of models, one with only a nonpulsatile left heart bypass, and the other with a pulsatile left heart bypass. In these experimental settings, we were also able to evaluate the changes of hormonal circadian rhythm. But we intended to focus on the effects of the reduction of pulsatility in a single individual. This setting was designed to assume the clinical situations that occur when a nonpulsatile blood pump is implanted in a patient with a native heart (of course with pulsatile flow), or in patients undergoing left heart bypass with a pulsatile ventricular assist device being exchanged for a nonpulsatile one, after which an adaptation of reduced pulse pressure circulation is applied. Consequently, it is a problem of priority in choosing which experimental setting we should use. For the issue of chronic versus acute studies, Dr. Ündar stated “The energy equivalent pressure formula will not be affected by the experimental conditions including anesthesia versus no anesthesia, or duration of support, or absence of pulmonary flow. Energy equivalent pressure is an excellent tool to quantify different modes of perfusion for direct comparison of any experimental designs as long as pressure and flow can be recorded.” Dr. Ündar has also misunderstood this point. We did not make any comments about the reliability of EEP. We mentioned that even if EEP is available under any experimental condition, it is only the reliability of the EEP formula itself, not the usefulness of EEP, to express the physiologic aspects under any condition. Whether the values of EEP really reflect physiologic effects is another problem. Physiologic change in any experiment is affected by the setting, including the choices of cardiopulmonary bypass or left heart bypass, anesthesia, surgical intervention, duration of support, absence of pulmonary flow, and so on. Accordingly, whether EEP is really useful to consider “physiologic problems” or not, should be shown by an evaluation of the “relationship between EEP and physiologic aspects.” In the previous letter of Dr. Ündar and associates, they stated, “Using the EEP formula, we have clearly shown that pulsatile perfusion generates significantly higher hemodynamic energy than nonpulsatile perfusion, and this extra energy may enhance vital organ perfusion.”4 However, they did not show the usefulness of EEP when considering the effects under reduced pulse pressure during prolonged left heart bypass, which are considered clinically important. The patient’s condition during left heart bypass is clearly different from that during temporary cardiopulmonary bypass. Dr. Ündar stated, “We believe that this formula (EEP formula) should be used when the investigators compare pulsatile versus nonpulsatile flow for short- or long-term support.” If that is so, then they should show scientific reasons for their belief. We would especially like to see evidence of the superiority of EEP as compared with conventional pulse pressure in a long-term reduced pulse pressure model under awake conditions. Our study, which was mentioned when it was stated that EEP should be used, employed such a model, and that condition is considered to be important as the application of long-term left heart bypass with continuous flow blood pumps is spreading. The scientific reasons for the superiority of a new method instead of a widely used conventional method must be shown in a convincing manner. We agree that pulse pressure has some limitations, and a new, better method is needed when considering “pulsatile and nonpulsatile” problems; we expect EEP to be such a one. We suppose that one of the reasons for these misunderstandings between Dr. Ündar and us is due to the ambiguous definitions of the terminology used. In our studies, “nonpulsatile left heart bypass” means “left heart bypass with a nonpulsatile blood pump,” not “left heart bypass with an almost zero pulsatility systemic pressure.” In “nonpulsatile left heart bypass,” the systemic pulse pressure is not necessarily zero pulse pressure, but reduced pulse pressure. To avoid misunderstandings like these in the future, we may have to use the phrases “continuous flow left heart bypass” and “left heart bypass with a continuous flow blood pump” including axial and centrifugal pumps. We thank Dr. Ündar for these discussions, and hope that this controversy is of some help in considering “pulsatile and nonpulsatile” problems for ASAIO Journal readers. T. Nishinaka E. Tatsumi T. Nishimura Y. Taenaka H. Takano