Introduction

An oxygenator failure (OF) during cardiopulmonary bypass (CPB) is a serious emergency. It is one of the leading causes of perfusion related accidents occurring in 0.09%-1.6% of CPB cases (₁, ₂). There is an 8.3% chance of experiencing significant morbidity or mortality during an OF event (₁). Clinically, an OF may present with an: abnormal trans-membrane pressure drop; deteriorating blood gases; declining venous or arterial saturation; reduced calculated oxygen transfer; or a visual indifference between pre and post oxygenator blood color. In this case study the authors present a unique mechanism that gives a presentation of an OF “syndrome”, which cardiac surgeons, anesthesiologists and perfusionists should consider in their troubleshooting algorhythm.

Description

A 70-year-old male patient presented with an enlarged aortic root. He had a previous aortic valve replacement (AVR) twelve years prior and a protracted history of hypertension. Elective redo AVR and aortic root replacement was undertaken. CPB was undertaken with an uncoated open circuit. Cold cardioplegia was administered in a 4:1 blood to crystalloid ratio. Venous saturation and hematocrit was monitored with a Cobe Saturation/Hematocrit monitor (Arvada, Colorado), which was calibrated at the start of bypass. Arterial flow rate range of 1.8 – 2.4 lpm/m ² was targeted dependent on temperature and venous saturation. Mean arterial blood pressure (BP) was managed at 40-60 mmHg. Activated clotting time (ACT) was maintained greater than 480 seconds during CPB.

Anaesthesia was induced in the usual fashion. Femoral venous and arterial cannulation was performed through surgical exposure followed by an uncomplicated sternotomy. After initiation of CPB and aortic crossclamping a one-liter dose of antegrade cardioplegia was administered. A retrograde cardioplegia catheter was placed providing an avenue for subsequent cardioplegia doses at twenty-minute intervals. Circulatory arrest ensued when the esophageal and bladder temperatures reached 18 C. A St. Jude aortic valved conduit (St Paul, Minnesota, USA) was inserted and sutured in the typical fashion. The patient was rewarmed to esophageal and bladder temperatures of 37 C. Deairing techniques were undertaken and the patient was weaned from CPB without incident. The CPB time was 250 minutes with a crossclamp time of 140 minutes and circulatory arrest time of 23 minutes. Ten minutes post sternal closure the patient experienced acute hemodynamic decompensation. The chest was emergently opened and cardiac massage initiated. The patient was heparinized, cannulated and CPB was reinstituted. A crossclamp was applied and antegrade cardioplegia administered. Transesophageal echocardiographic evaluation revealed a small amount of air in the pulmonary veins and left atria. Multiple attempts over a two hour and twenty minute time span to wean off CPB were unsuccessful due to refractory hypotension. During this time the venous saturation monitor was functional and obvious visual arterialization of the blood was taking place post oxygenator. At approximately two hours and twenty-two minutes after the emergent initiation of CPB both authors observed the acute darkening of the blood post oxygenator. The color appeared black, which the authors describe as being similar to venous deoxygenated blood. There was overt blood color indifference between pre and post oxygenator. The venous saturation monitor's numerical values began to plummet and displayed dash lines. In response, the FiO2 was increased to 1.00, an ABG was drawn and sent for analysis, and gas lines were examined to confirm gas flow. No mechanical abnormally was noted; therefore, the authors announced to the OR staff that there may be an OF and preparations were instituted for an oxygenator change-out. Immediately, the anesthesiologist announced that 2 mg/kg of methylene blue (MB) had just been bolused through the central line. At approximately five minutes from the MB bolus the ABG results arrived from the blood gas sample drawn at the initiation of the possible OF and depicted a PaO2 = 528 mmHg. As a result, the authors decided to postpone undertaking an emergent oxygenator change out. Approximately, six to eight minutes after the administration of MB the venous saturation monitor abruptly displayed numeric values and the post oxygenator blood returned to bright red. The remainder of the CPB was technically unremarkable with subsequent ABG's depicting PaO2 518 mmHg with a normally functioning venous saturation monitor. Eventually, the patient was incapable of being separated from CPB and was placed on a left ventricular assist device (LVAD). After LVAD placement the patient was weaned from CPB and transferred to the intensive care unit. The total CPB time was six hours ten minutes. Unfortunately, the patient required the addition of a right ventricular assist device on postoperative day one and died postoperative day three.

Comment

Methylene blue (MB) is a phenothiazinium compound with numerous clinical applications. MB is a recommended treatment modality for methmoglobinemia (MHb) (₃). At therapeutic doses of 1 – 2 mg/kg, MB aids in the reduction of the iron moiety in the red cell through the nicotinamide-adenine-dinucleotide-phosphate methemoglobin-reductase pathway and the conversion of MB to leucomethylene blue (LB). MB has also shown promise in the photodynamic treatment of various tumors (₄). A 1 – 2 % aqueous solution of MB injected into tumor cells is capable of absorbing extraneous light and producing reactive oxygen species to create a cytotoxic effect (₅). The blue dye staining effect observed with MB is useful for tracking urine flow in various urologic procedures (₆). Ifosfamide encephalopathy and malaria can be responsive to MB administration as well. MB has also been applied in the perioperative and postoperative cardiac surgery population to treat catecholamine refractory hypotension, referred to as vasoplegia syndrome (VS) (₇, ₈).

VS is a condition defined by an BP < 50 mmHg, CI > 2.5 L/min/m ² , right atrial pressure < 5mmHg, left atrial pressure < 10 mmHg, and a systemic vascular resistance (SVR) < 800 dynes/second/cm ⁵ during a norepinephrine infusion > 0.5 mcg/kg/min (₇). The incidence of VS in the cardiac surgery population has been reported to be approximately 8-10% (₉). The development of VS associated with CPB is not well understood; however, a proposed mechanism is the CPB activation of proinflammatory mediators and the activation of nitric oxide and non-nitric oxide induced guanylate cyclase (GC) and the subsequent upregulation of cyclic guanosine 3,5 monophosphate (cGMP) mediated vasodilation (₉). However, VS is not specific to CPB and has been reported in off-pump coronary artery bypass surgery (₁₀).

The first reported use of MB to treat refractory hypotension during CPB was by Grayling and Deakin (₁₁). However, the first large clinical trial to report the successful use of MB in VS patients was presented by Lehy et al. (₁₂). A MB dose of 1.5 - 2 mg/kg administered intravenously has been used to successfully treat VS (₉). The suspected pharmacological action of MB is mediated through the drugs capacity to bind to the iron moiety of GC resulting in the inhibition of GC, cGMP and vasodilation (₉). There has been a recent literature review and case report of MB and CPB (₁₃). This paper implicates MHb formation after the administration of MB during CPB as a potential cause of declining saturation and darkening of the post oxygenator blood. However, a second case described in the paper demonstrates that the co-oximetry results during MB administration depict no acute MHb formation with associated black post oxygenator blood. While it is has been reported that large doses of MB ( 4 mg/kg) can produce a paradoxical MHb (₃), we propose an alternate theory that mimics the “syndrome” of an OF.

Saturation monitors work through the emission of two wavelengths of light of approximately 640 nm and 940 nm. The device performs a calculation based on the ratio of the absorbance of the two wavelengths (640 nm / 940 nm). It compares this value to the reference values entered into the monitor from empirical and co-oximeter data obtained from healthy individuals used to calibrate the device. From this the saturation monitor will display a numerical saturation value. The limitation of these devices is that they cannot differentiate dysfunctional hemoglobin from functional hemoglobin. In the presence of dysfunctional hemoglobin a saturation monitor will not provide accurate or reliable results of oxygen bound hemoglobin concentrations. When MHb is present the displayed numerical saturation values will approximate 82% - 86% irrespective of the blood concentration level of MHb (₃). This result stems from MHb having the property of equal absorbance of 660 nm and 940 nm light wavelengths. Therefore, the 640 nm / 940 nm ratio will equate to a value of 1.0 translating into a displayed value of approximately 85%. In our patient, the venous saturation monitor began a precipitous drop from displaying numerical values to dashed lines (venous saturation 50%) within seconds of noticing the blood color indifference pre and post oxygenator. It is important to state, however, that a numerical saturation value below 82% may indicate the presence of deoxygenated hemoglobin in conjunction with MHb. While the actual numerical value will not be accurate of the concentration of deoxygenated hemoglobin it may be an indication of a coexisting MHb and deoxygenated functional hemoglobin (₃). In our patient, the ABG drawn during the event had a PO2 = 528 mmHg, indicating the absence of inadequate oxygen transfer; thereby, minimizing the possibility of associated desaturation of functional hemoglobin causing the plummeting venous saturation displayed values. MHb cannot be absolutely ruled out as a cause of the declining saturation, however, it is suspect given the aforementioned effect that MHb has on saturation monitors.

Furthermore, after injection MB remains non-protein bound and is freely distributed throughout body compartments (₆). MB will absorb light at a wavelength of 550 – 700 nanometers (nm), with a preferential absorption at approximately 660 nm (Figure 1.) and will MB falsely lower oximeter values (₆, ₉).

Figure 1

Figure 1: Light Absorption of Methylene Blue

Visible light has a wavelength of 380 nm – 750 nm with blue-green-violet spectrum of approximately 400 nm – 570 nm, and orange-red light spectrum of approximately 590 nm – 750 nm. MB preferentially absorbs the orange-red spectrum and produces a blue-green color visible in the CPB circuit. The authors describe the blood color throughout the entire CPB circuit as “black” or “desaturated venous blood” during the potential OF, which appeared as a blood color indifference pre and post oxygenator. This color description is not inconsequential. It has been reported that a classic presentation of MHb is “chocolate-brown” blood (₃). The black color is supported by the explanation of MB's light absorption properties. The overt visual color indifference between pre and post oxygenator blood persisted for approximately six to eight minutes during the suspected OF event. The reported half-life of MHb is approximately 1 hour in non-CPB patients (₁₃). The pharmacokinetics of MB during CPB has not been described. CPB involves numerous non-physiologic aspects including hemodilution, blood-surface interface and altered organ physiology. The extrapolation of MB kinetics with the use CPB may not be applicable from the non-CPB population. We suspect that the six to eight minutes it took for the resolution of the visual effects of MB was a result of possible absorption within the CPB circuit components, redistribution within the patient, and MB metabolism. In support of the circuit absorption mechanism the authors observed a prevalent green-blue staining along the entire length of the arterial and venous cannulae after decannulation. To our knowledge the absorption of MB in CPB circuit components has not been described and is an area that warrants investigation.

The biotransformation of MB takes place in the red blood cell to LB. LB has a light absorption preference of 260 nm. Since the absorption spectrum of LB is outside the range of the saturation monitor wavelength emission the accuracy of the device should not be affected. However, this also needs to be studied formally.

Therefore, the plummeting venous saturation values combined with black or blood color indifference pre and post oxygenator may be explained by the physical properties of circulating MB and the limitations of the monitoring equipment. While we do not rule out acute MHb formation to mimic an OF, we do propose an alternate theory.

In retrospect the authors could have drawn simultaneous venous and arterial blood gases and calculated oxygen transfer. This would be a definitive step in eliminating an OF as a source of the observed events. Given that the ABG analyzer was not housed within the operating room, which somewhat delayed the return of the results, this may be an insignificant point. However, at centers with point of care ABG analyzers contained in the OR this may be an important step in an OF assessment protocol.

A situation involving an OF is an emergency. The recognition of the signs of an OF and the actions taken to eliminate the possible factors responsible for the inability to oxygenate the blood is paramount. Communication and vigilance is required on part of the cardiac surgeon, anesthesiologist and perfusionist. It is proposed in this case report that the unannounced bolus of MB needs to be considered as a possible source for mimicking an OF, which does not necessitate an emergent oxygenator change out. The physical properties of MB can produce a “syndrome” similar to an OF.