TRANSMEMBRANE PRESSURE DIFFERENTIALS (TMPD)

The general opinion in perfusion over four decades ago was that high pressure differentials in oxygenators were associated with dramatic increases in hemolysis. Unfortunately, this same opinion seems to still be prevalent in our perfusion education today… despite a lack of clear in vivo or ex vivo hematological evidence to support these claims. However, two separate surveys found a majority of North American centers surveyed did not measure trans-membrane pressure differentials during CPB, with most electing to measure postmembrane pressures only (Myers GJ, 2003, Rigg L, 2014). Apparently, this continues to be the case in most North American perfusion programs. Some marketing strategies still focus on the benefit of a devices lower pressure differential, and caution about the presence of higher trans-membrane pressure differentials (TMPD) during Extracorporeal Circulation.

But what evidence is there that a TMPD of let’s say, 100 mmHg at a bypass flow of 4.0 LPM, produces more clinically harmful levels of hemolysis than a TMPD of 50 mmHg at the same flow? In addition to gaseous microemboli (GME), are there any other potential clinical benefits to having higher pressure differentials within the membrane compartment during extracorporeal circulation? Adding uncertainty and confusion to this issue of TMPD and hemolysis in membrane oxygenators, are studies that compare relatively uniform blood pump flows with devices that have vastly different blood contact surface areas and manufacturers rated blood flows. For example, it would appear obvious that TMPD and plasma free hemoglobin data are not clinically or even statistically valid or comparable when investigators (Undar A, 2005) run blood flows of 400-600 mls/min through one membrane that has a maximum rated flow of 800 mls/min (50-75% of rated flow), and then compare the results obtained to those same blood flows (400-600 mls/min) put through another membrane that has a maximum rated flow of 4000 mls/min (10-15% of rated flow.?

Combine the latter type of reports with in vivo clinical studies that incorporate variables such as cardiotomy suction and venting … and the conclusions get even more ambiguous. When it comes to reading through the literature regarding the topic of trans-membrane positive pressure differentials and hemolysis, there seems to be a common belief that a TMPD greater than 100 mmHg is harmful to blood and has the potential to increase hemolysis in membrane oxygenators to critical levels. However, when we track down the original references related to that conclusion, it appears that the 100 mmHg pressure differential may have originally come from an investigation into cannulas (not membrane oxygenators) and hemolysis over 62 years ago … not membrane oxygenators. The authors of the book (Galletti & Brecher, 1962) discussed the relationship between varied flow rates through cannulas and the increasing plasma free hemoglobin levels when 'cannula pressure differentials' exceeded 100 mmHg. Somehow, through the years, it appears that this cannula pressure differential was then used as a standard reference of impending hemolysis in membrane oxygenators as well.

This historical confusion over data between cannulas and oxygenators has generated a great deal of uncertainty amongst clinicians and created a tremendous marketing tool for the manufacturing industry. Unfortunately, even when it does come to cannulas, in 1962 those same authors were not focusing on other causes of hemolysis related to those cannulas being investigated, such as shear stress, turbulence, stasis and cavitation which as we know today are all significant contributors to clinical hemolysis. During an ex vivo study (Kawahito S, 2001) investigating four different membrane oxygenators, from low resistant to high resistant, [with isolation of the cardiotomy suction blood], the authors found TMPD’s ranged between 78 - 171 mmHg, while the Normalize Index of Hemolysis (NIH) values only varied between 0.01 - 0.04 gm/100L (normal < 0.04 gm/100L). Another report (Gu YJ, 2000) found that high positive pressure differentials and high shear stresses were found with the flat plate oxygenators they tested, which seemed to correlate with the release of Elastase and leukocyte activation (through shear stress response) at the end of bypass. However, the authors in this same study were unable to find similar results in the hollow fiber oxygenators they tested. Obviously, in modern membrane oxygenators, flat plate technology is no longer on the market.

During an ex vivo investigation into pressure drops and hemolysis in three membrane oxygenators (Bearss MG, 1993) the authors concluded that there was no evidence to support a relationship between increased TMPD and excessive hemolysis in hollow fiber membrane oxygenators. The author stated that hemolysis produced by positive pressure drops in membrane oxygenators is clinically negligible, especially when compared to the hemolysis produced through negative pressures in cardiotomy suction. Voorhees M, 1996 suggested that higher pressure differentials may be better for removal of GME from membrane oxygenators due to the increased pressure gradient exerted upon the hollow fibers between the blood compartment and the gas flow compartment. This was a similar finding by Myers GJ, 2012) during an ex vivo study involving several different hollow fiber membranes. A new investigation into GME and TMPD (Condello I, 2024) found that lower TMPD demonstrated significantly higher amounts, sizes and volumes of gaseous microbubbles post membrane, than those membranes with higher TMPD.

In fact, if the TMPD were zero, almost all GME entering the membrane compartment would subsequently exit the membrane compartment through the hollow fibers because of the absence of a pressure differential. DeSomer F, 2007 stated that the mechanism for removing GME in microporous membrane oxygenators is based on the reduction in blood velocity within the membrane compartment and the blood contact time with hollow fibers. Matsuda N, 2000 found that the membranes axial jacket length and its subsequent increase in pressure drop also led to an increase in oxygen transfer within the membrane compartment.

Segars P, 2001 investigated pressure drop and hemolysis in 90 patients undergoing coronary artery bypass grafts (CABG), using nine different low resistant and high resistant hollow fiber oxygenators [isolation of cardiotomy suction blood]. The authors found that during hypothermia the range of TMPD in the nine devices was 98 to 199 mmHg, and during rewarming the range of pressure drop was 103 to 186 mmHg. The Plasma Free Hemoglobin (PFH) findings ranged from 1.3 to 8.4 mg/dl (normal ?< 30 mg/dl), with an average blood flow during bypass of 4.2 ± 0.5 LPM. The authors concluded that higher pressure drops did not result in any significant increase in hemolysis. Simons AP, 2010 did a similar in vivo investigation into TMPD and hemolysis during the application of pulsatile flow. They investigated 33 patients undergoing elective CABG surgery with two types of low resistant and high resistant membrane oxygenators, using a pulsatile flow set at 5.0 LPM and a frequency of 72 bpm (pulse width of 50%). During pulsatile perfusion, the average TMPD for the low resistant oxygenators was 619 ±28 mmHg with a peak of 820 mmHg, and the average TMPD for the high resistant oxygenators was 827 ±53 mmHg with a peak of 1250 mmHg. The authors found that even though NIH values were elevated above normal during pulsatile flow and very high pressure drops in both the high resistant oxygenator (NIH 0.10 ± 0.088 g/100L) and the low resistant oxygenators (NIH 0.09 ± 0.074 g/100L), there was no significant difference in the NIH values (p=0.04) between the two types of membrane design. Unfortunately, the authors did not measure shear stress associated with the pulsatile flow and membrane design.

The most recent investigation to determine if pressure drop was an independent risk factor for hemolysis in modern membrane oxygenators was done by Venema LH, 2014, that included an analysis of the oxygenator shear stress and intra-oxygenator blood flow distribution. This ex vivo investigation compared the data found in one brand of low resistant oxygenator (Quadrox i), one brand of medium resistant oxygenator (RX15) and one brand of high resistant oxygenator (Inspire 6). The flow rates for each device were set at 2 LPM, 4 LPM and each manufacturer maximum rated flow rate, with PFH and NIH analysis done every 30 minutes. The TMPD was found between 14-41 mmHg in the low resistant device, 29-115 mmHg in the medium resistant device and 77-284 mmHg in the high resistant device. Considering all devices tested, the NIH values ranged between 0.0015 gm/100L and 0.007 gm/100L (normal is 0.1 g/100L). At the maximum rated flow for each device tested (5.0, 6.0 and 7.0 LPM), shear stress was found to be 30 dynes/cm2 (3.0 N/m2) in the low resistant device, 57 dynes/cm2 (5.7 N/m2) in the medium resistant device and 84 dynes/cm2 (8.4 N/m2) in the high resistant device. Red blood cell hemolysis occurs when shear stress >1500 dynes/cm2 and sub-lethal red blood cell damage does not occur until shear stress levels are between 210 dynes/cm2 and 430 dynes/cm2. Their analysis of blood flow distribution curves revealed that intra-oxygenator blood flow becomes more homogenous as blood flow increases, independent of their differences in pressure drop. The authors concluded that TMPD is not an independent risk factor for hemolysis in modern membrane oxygenators.?

In a review of oxygenator design and the relationship between pressure drop and hemolysis, DeSomer F, 2013 concluded that based on existing data in the literature as well as on basic physics, hemolysis is not determined by an oxygenators TMPD. When it comes to positive pressure differentials, far too often is clinical practice influenced by the unknown and the unproven clinical opinions, but evidence-based literature often exposes exaggerated claims about TMPD based on historical information and anecdotal evidence. During clinical or prolonged extracorporeal circulation, hemolysis of flowing blood does not occur even when exposed to positive pressures of 1000 mmHg (Chambers SD, 1996 and Chambers SD, 1999).

To summarize this article on positive pressure differential concerns around red blood cell hemolysis in the presence of higher TMPD, current evidence-based literature indicates that all design dependent effects on TMPD in axial flow, radial flow, and cross flow membrane oxygenators, is not a concern for hemolysis or sub-lethal red cell damage in any modern membrane oxygenator. However, it does appear that high resistant membrane bundle oxygenators will improve the removal of GME through the hollow fibers, and possibly increase oxygen transfer within the membrane compartment.

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