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Case Report

Endogenous Carbon Monoxide Production: A Rare and Detrimental Complication of Extracorporeal Membrane Oxygenation

Hermans, Greet*; Wilmer, Alexander*; Knockaert, Daniel*; Meyns, Bart

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doi: 10.1097/MAT.0b013e318185e1e6
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Case Report

A 39-year-old patient with end-stage pulmonary fibrosis due to histiocytosis X, was already on the urgent transplantation list when he developed acute respiratory insufficiency due to a spontaneous pneumothorax, for which he was urgently intubated and a chest drain was placed. Subsequently, he was transferred to our Intensive Care Unit (ICU). Over the next 24 hours, the patient developed severe hypoxia (paO2/FIO2 ratio 39 mm Hg) with prominent air leakage despite good expansion of the lung. At this point, extracorporeal membrane oxygenation (ECMO) was started by femoral veno-venous access (using a vena femoralis inflow cannula of 29 French and an outflow vena femoralis canula 27 French, both Medtronic Biomedicus Carmeda coated cannulae), which markedly improved oxygenation (paO2/FIO2 ratio 119 mm Hg). We used a centrifugal pump; Biomedicus, Medtronic, MN, and oxygenator Medos Hilite7000LT. The whole circuit was Medtronic Carmedo coated. On day 5 after ICU admission, the patient developed a septic shock complicated by ischemic hepatitis, treated with fluids, vasopressor drugs and antibiotics. Over the next 24 hours, the patient’s condition improved and vasopressor therapy was stopped. Therapy with inhaled nitric oxide (NO) was started because of significant pulmonary hypertension which improved oxygenation (PaO2/FIO2 rose from 54 to 67 mm Hg with the same ventilatory and ECMO settings). On day 9 of ICU stay, the patient developed a cardiogenic shock requiring massive doses of inotropic and vasopressor drugs due to dilatation of the right ventricle with compression of the left ventricle. Therefore, the ECMO access was switched to a veno-arterial setting using the two existing canulae as the efferent system and implanting a third canula (21 French, Medtronic Biomedicus Carmeda coated) on the femoral artery using a graft. Inotropics and vasopressors were discontinued quickly after this intervention. However, during the following days, high flow rates creating high premembrane pressures were required to ensure adequate oxygenation, which resulted in significant hemolysis. Carboxyhemoglobin (COHb) levels rose up to 4.4% on day 13 of ICU stay, which urged us to reduce and eventually stop NO therapy. However, the COHb level continued to rise up to 9.5%. On day 18, the patient was transplanted, still on ECMO, but did not survive the operation due to massive pleural bleeding and hemorrhagic shock.


Carbon monoxide (CO) is an exogenous poison that binds hemoglobin with a much higher affinity than oxygen and, therefore, displaces oxygen from hemoglobin. At the same time, it increases the affinity of the remaining sites for bound oxygen. This results in a reduced oxygen transport capacity and decreased release of oxygen to the tissues. It is, however, less known that CO is produced endogenously during the normal catabolism of hemoglobin. Hemoxygenase (HO) enzymes break down heme molecules into free iron, biliverdine and CO. HO enzymes exist in different isoforms: inducible HO-1, and constitutive HO-2 and HO-3. HO-1 is induced by its substrate heme and a number of other agents that cause oxidative stress (e.g., hypoxia, hyperoxia, acute lung injury, sepsis, and NO).1–3

The levels of COHb of up to 9.5% in this patient clearly exceeded the slightly increased levels (0.8%–2%) that have been reported in critically ill patients.1,4,5 Therapy with NO has been associated with increased levels of COHb due to induction of HO by NO and production of methemoglobin, releasing heme.2 Therefore, therapy with NO was reduced and subsequently stopped. Despite this intervention, COHb levels kept rising. Importantly, significant hemolysis became apparent after switching the ECMO access route from veno-venous to veno-arterial, reflected by increased levels of bilirubin, lactate dehydrogenase (LDH) and free hemoglobin (Figure 1). As evidenced by an excess of fragmentocytes, hemolysis was due to mechanical trauma, a well-known complication of ECMO,6 that is determined by shear forces, turbulence and blood flow velocity. Blood clots in the circuit can also cause hemolysis.7 This was ruled out by daily checks of the circuit. The patient was 1.84 m and weighed 76 kg. The cannulae were appropriately sized for this patient, and therefore unlikely to have been a cause of hemolysis. The gradual increase in ECMO flow needed to maintain adequate oxygenation resulted in very high premembrane pressures and worsened hemolysis. COHb levels paralleled the increase in hemolysis parameters. As heme is a potent inductor of HO, we concluded that the massive hemolysis most likely caused the elevated COHb levels. Moreover, the slight decrease in ECMO flow noticed during day 17 of ICU stay, coincided with lower mean premembrane pressures and a small decrease in COHb on day 18.

Figure 1.
Figure 1.:
Laboratory and extracorporeal membrane oxygenation (ECMO) characteristics during intensive care unit (ICU) stay. During ECMO treatment an increase in carboxyhemoglobin (COHb), LDH, Bilirubin and free hemoglobin became apparent. Pre and postmembrane ECMO pressures also increased with a fairly steady flow. Nitric oxide (NO) treatment was given between day 5 and day 14.

Other factors such as sepsis and oxidative lung stress may also contribute to COHb production. However, it seems unlikely that these were major determinants in this case, as the first episode of sepsis was quickly controlled, and a second inflammatory episode occurred on day 15 after ICU admission, after a significant rise in COHb had already been documented. Oxidative stress in the lung was already present long before the rise in COHb. Transfusion of packed cells is another potential direct source of COHb.8 A random check of administered packed cells revealed the absence of detectable COHb levels. Therefore, the high level of 9.5% in this patient was unlikely the result of transfusion.

The presence of up to 9.5% COHb might have been detrimental in this patient as it obviously reduced oxygen transport capacity and tissue oxygenation.2 The cause of the massive hemolysis remains somewhat elusive. High postmembrane pressures and a normal pressure drop over the membrane indicate that there was no oxygenator problem. Postmortem evaluation of this case by the ECMO team suggested that the increasing resistance in the afferent system might have resulted from the implantation of the cannula at the graft and reintervention might have been beneficial.


We report on a patient who developed significant levels of COHb, most likely caused by massive mechanical hemolysis due to ECMO. This may be detrimental in patients with an already limited tissue oxygen supply. We suggest that COHb should be routinely checked in patients treated with ECMO. If a rise is detected and mechanical hemolysis is obvious, careful analysis of the pressures at different sites of the circuit should enable physicians to locate the problem and act accordingly.


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