Use of Hemoadsorption in Patients With Severe Intoxication Requiring Extracorporeal Cardiopulmonary Support—A Case Series

Abstract

Drugs intoxications often lead to severe vasoplegia and cardiogenic shock, and VA-ECMO represents a viable therapy option. However, as cardiopulmonary support is not contributing to the removal of the causal agent from the blood, detoxification by a new hemoadsorption device (CytoSorb) could represent a potential therapeutic tool due to its highly efficient elimination capacity of endogenous but also exogenous hydrophobic substances for which otherwise no effective antidote exist.

In this case series, four anecdotal cases of acute intoxications requiring VA-ECMO support used as extracorporeal cardiopulmonary resuscitation after intoxication-induced out-of-hospital cardiac arrest (OHCA) are presented, who were additionally treated with CytoSorb hemoadsorption in combination with renal replacement therapy. Combined treatment was associated with a considerable decrease in plasma levels of the overdosed drugs. Additionally, the combination of applied techniques was safe, practical, and technically feasible with no adverse or any device-related side effects documented during or after the treatment sessions.

Based on the reported dramatic decline in drug levels during treatment, that fits in the device’s characteristics, we strongly suggest to further investigate the potentially lifesaving role of CytoSorb therapy in patients with acute intoxications requiring multiple organ support techniques.

Intoxication-induced Out-of-Hospital Cardiac Arrest (OHCA) represents a major medical challenge with a growing number of cases.¹ In recent years, veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) used as extracorporeal cardiopulmonary resuscitation (eCPR) has gained increasing importance as the bridging option in OHCA patients until subsequent treatment can be applied. Drugs intoxications often lead to severe vasoplegia and cardiogenic shock, and VA-ECMO represents a viable therapy option.² However, in the case of intoxication, cardiopulmonary support is not contributing to the removal of the causal agent from the blood, and detoxification approaches have been simultaneously applied with only moderate success.³ Importantly, in many cases, the causative agent is unknown or its classification problematic or time consuming, making it difficult to apply an appropriate antidote, thereby posing a considerable challenge to physicians and caregivers. In such situations, gastrointestinal decontamination, plasma exchange, inhibition of enterohepatic-reabsorption, and the intravenous infusion of lipid emulsions represent the methods of choice.^4,5

Recently, a new hemoadsorption device (CytoSorb, CytoSorbents Corporation, Monmouth Junction, NJ) has gained increasing attention predominantly in the fields of critical care and cardiac surgery. This adsorber consists of polymer beads capable of removing molecules up to around 55 kDa from whole blood in an unspecific, broad-spectrum manner. In conditions such as systemic hyperinflammation, reduction of excessive inflammatory mediator levels is desired; however, the potential elimination of a therapeutic drug remains a plausible concern when applying this technology. On the other hand, in the field of intoxication, the highly efficient elimination of potentially deleterious drug levels is highly desired, and it is here that CytoSorb could represent a potential therapeutic tool for the treatment of intoxications. Importantly, evidence in this indication remains sparse.⁶

Since 2014, more than 400 patients have been admitted to our center in a condition of OHCA and in which the use of eCPR has been evaluated. Of these, 180 patients were finally treated with eCPR. Given the potentially beneficial effects of CytoSorb hemoadsorption in patients with intoxications and based on the reported feasibility and safety of the integration of this device into ECMO^7–9 and even more so into renal replacement circuits, we hypothesized that the combined use of those measures could help to deplete toxic drug levels and to stabilize patients.

We herein describe 4 patients with cardiocirculatory arrest or cardiogenic shock due to intoxication who were treated with CytoSorb and VA-ECMO. Patient information were collected routinely according to local data protection in our center. According to local law, no formal institutional review approval by the ethics committee of Charité Universitätsmedizin Berlin was required for retrospective scientific analysis of own patient data.

Case 1

This case reports on a 54-year-old female patient who had ingested 250 mg bisoprolol and 500 mg amlodipine in an attempt at suicide. The next morning the patient called for help and a neighbor alerted the fire brigade. Upon arrival of the emergency physician, the patient was found hypothermic (34.1°C) with a heart rate of 40/min and a systolic blood pressure of 65 mm Hg. Subsequently, she was transferred to the intensive care unit of a peripheral hospital and had to be intubated due to respiratory insufficiency and hemodynamic instability. Sinus rhythm converted into pulseless electrical activity (PEA). The following cardiopulmonary resuscitation resulted in a return of spontaneous circulation (ROSC) after 15 minutes. Administration of glucagon i.v. was commenced followed by administration of active charcoal, lipids, and initiation of continuous renal replacement therapy (CRRT). The patient went on to develop severe cardiogenic shock requiring extremely high dosages of catecholamines (epinephrine, norepinephrine) as well as vasopressin and levosimendan. Subsequently, given her refractory shock state, VA-ECMO (Cardiohelp, Maquet, blood flow >4 L/min, gas flow according to blood gas analysis) was implanted on site by the ECMO team, and the patient was then transferred to the Charité Hospital.

As the amlodipine levels remained high, a CytoSorb hemoadsorber was integrated into the running CRRT circuit (Multifiltrate, Fresenius Medical Care, blood flow rate 100 ml/min, dialysate flow 2000 ml/h) installed in predialyzer mode following the recommended priming and integration procedure according to the manufacturer’s instructions.¹⁰ This resulted in a decrease in plasma amlodipine levels. To enhance the detoxification process, plasma exchange was performed twice; however, without noticeable effect. Therefore, CRRT was switched back to citrate-anticoagulated continuous veno-venous hemodialysis (CVVHD) plus CytoSorb hemoadsorption (Figure 1; Table 1).

Table 1. - Patient Characteristics, Time on VA-ECMO, and Outcome

Patient No.	Age	Gender	Intoxication	Days on VA-ECMO	Cerebral Performance Category	Outcome
1	54	F	500 mg Amlodipin + 250 bisoprolol	7	2	Discharge to rehabilitation unit
2	60	M	4 g Amitryptilin	4	1	Discharge to rehabilitation unit
3	61	F	450 mg Bisoprolol + amlodipin (amount unknown)	/	/	Death
4	57	F	Amlodipin (amount unknown)	5	1	Discharge to rehabilitation unit

Figure 1.: Course of plasma drug levels over time for all 4 patients under combined VA ECMO, CRRT, and CytoSorb treatment. Please note that the scale of the X-axis is not proportional.

Three days after admission, the patient developed lower limb ischemia due to dissection of the femoral artery, most likely caused by the inaccurate insertion of the backflow cannula. She subsequently developed compartment syndrome followed by fasciotomy and later amputation of the lower leg. The ECMO could be explanted 7 days after implantation, and CytoSorb was also discontinued, while CRRT was stopped 1 day later. She was transferred to the normal ward hemodynamically stable with no neurologic deficit 2 months after the initial overdose. Renal function was still slightly impaired [glomerular filtration rate (GFR) 35 ml/min], however, without the necessity for dialysis at the time of discharge.

Case 2

A previously healthy 60-year-old male patient was found by the emergency physician after he lost consciousness at home, followed by an emergency call made by his wife, who later found several empty blister packages of the tricyclic antidepressant amitriptyline (assumed ingestion of 4 g). A farewell letter was found next to the patient indicating a suicidal attempt.

Upon initial preclinical examination, the patient showed a Glasgow Coma Scale (GCS) score of 5; however, he was not hemodynamically compromised. Shortly thereafter, the patient lost consciousness and suffered circulatory arrest. Former sinus rhythm converted into bradycardic PEA, and CPR was immediately initiated followed by transfer to the hospital via the emergency ambulance. The patient arrived at the intensive care unit (ICU) receiving ongoing CPR, which had been underway for 55 minutes due to persistent PEA.

After implantation of a femoro-femoral VA-ECMO (85 minutes after the start of CPR), the patient had a ROSC as detected by arterial blood pressure monitoring. To inhibit the enterohepatic-reabsorption of amitriptyline, charcoal was administered using a gastric tube. Transesophageal echocardiography revealed a normal left ventricular ejection fraction (LVEF) and no localized dysfunctions.

For additional amitriptyline elimination, the decision was made to start CVVHD combined with a CytoSorb hemoadsorber (predialyzer position) for enhanced removal. Combined treatment was performed using citrate anticoagulation with a blood flow rate of 100 ml/min and a dialysate flow of 2000 ml/h, again following the recommended priming and integration procedure according to the manufacturer’s instructions.¹⁰ In total, five CytoSorb adsorbers were used and changed every 24 hours.

Following initiation of CVVHD combined with CytoSorb, the serum amitriptyline levels declined rapidly and four days after admission levels were in the therapeutic range so that CytoSorb-CVVHD-therapy was discontinued (Figure 1; Table 1). Weaning from the VA-ECMO was started out 3 days after admission, and VA-ECMO could be explanted after a total of 5 days. Hemodynamics remained stable thereafter. Two days later, the patient could be extubated. Twenty-three days after initial admission, the patient was discharged with a Cerebral Performance Category (CPC) score of 1 and normal renal and liver function.

Case 3

A 61-year-old female patient was admitted to a peripheral hospital after intoxication with presumably 90 tablets of 5 mg bisoprolol and possibly also of amlodipine and metformin. As circulatory failure progressed despite maximum catecholamine therapy with norepinephrine (2 µg/kg/min) and epinephrine (1 µg/kg/min), administration of 10 mg glucagon (fractionated) as well as application of a temporary pacemaker and use of charcoal, the decision was made to transfer the patient to our ICU for further management. Intubation was already done by the referring hospital. Transthoracic echocardiography revealed a remaining left ventricular ejection fraction of 10%–20%. Directly after admission, the patient went into cardiac arrest. ROSC was achieved after 5 minutes. Vasoplegia in the context of cardiogenic shock progressed, followed by the addition of vasopressin to maximal norepinephrine and epinephrine therapy. At that time, her pH was 7.14 and plasma lactate levels were 6.1 mmol/l. Subsequently, ongoing hemodynamic stabilization could not be achieved by conventional measures; hence, the patient was put on femoro-femoral VA-ECMO.

With the rationale to eliminate toxic drug peak levels, CVVHD with MultiBic solution (potassium-free; as possible intoxication with metformin represents a contraindication for regional citrate anticoagulation) was initiated supplemented by a CytoSorb adsorber integrated in predialyzer position (priming and integration procedure see reference 10 for CRRT). Blood flow was set to 150 ml/min and dialysate flow to 3 L/h, which was later raised to 200 ml blood flow and 4 L dialysate flow. During treatment, amlodipine levels dropped from 280 on admission to 149 ng/ml and bisoprolol dropped from 268 to 105 µg/l after 18 hours of CytoSorb-CVVHD (Figure 1; Table 1). Metformin levels were not measured.

Subsequently, the patient developed progressive lactate acidosis and rhabdomyolysis, possibly due in part to tissue ischemia before VA-ECMO implantation. Even though angiographic examination had shown adequate perfusion of the lower limbs, the patient developed compartment syndrome and a fasciotomy had to be performed. Twenty-six hours after admission to our ICU, the patient died from multiorgan failure and severe lactic acidosis.

Case 4

This case reports on a 57-year-old female patient, who was found by the emergency physician with severe hypotension following ingestion of an unspecified amount of unknown drugs in a suicidal attempt. Due to the development of acute respiratory insufficiency, the patient had to be intubated and mechanically ventilated. After subsequent transfer to a peripheral hospital, her hemodynamics could not be sufficiently stabilized due to severe vasoplegia and despite maximum doses of norepinephrine (2 µg/kg/min), epinephrine (0.5 µg/kg/min), dobutamine (1.3 µg/kg/min), and vasopressin (2.3 U/h). Additional glucagon therapy had no impact either. Therefore, a femoro-femoral VA-ECMO was instituted with a blood flow of 5 L/min, and the patient was subsequently transferred to the Charité Berlin for further therapy. Transthoracic echocardiography showed normal left ventricular (LV) function and right ventricular (RV) function. As intoxication seemed probable, combined treatment with citrate-anticoagulated CVVHD and CytoSorb (predialyzer position, priming, and integration procedure, see reference 10 for CRRT) with a blood flow rate of 100 ml/min and a dialysate flow of 2000 ml/h was started to treat drug intoxication of unknown origin. Over time, toxicology diagnostics revealed intoxication with amlodipine (426 ng/ml, therapeutic range 5–15 ng/ml). CytoSorb adsorbers were changed every 24 hours. After 4 days, amlodipine levels dropped to 78 ng/ml and CVVHD-CytoSorb therapy was stopped (Figure 1; Table 1). After a further 24 hours, VA-ECMO therapy was stopped. Thereafter, the patient remained stable and was later discharged with good neurologic function.

Discussion

In this case series, we presented 4 anecdotal cases of acute intoxications requiring VA-ECMO support used as extracorporeal cardiopulmonary resuscitation after OHCA, who were additionally treated with CytoSorb hemoadsorption in combination with renal replacement therapy. Combined treatment was associated with a considerable decrease in plasma levels of the overdosed drugs. Additionally, the combination of applied techniques was safe, practical, and technically feasible with no adverse or any device-related side effects documented during or after the treatment sessions.

Although application of the CytoSorb hemoadsorption device in intoxications per se represents an off-label use, several case reports have opened the field for this approach for not only being able to reduce endogenous mediators but also to eliminate exogenous compounds from blood for which otherwise no effective antidote exists.

In vitro analyses have shown that the removal of various drugs from the blood is possible.^11,12 However, also clinical data provide decent evidence for a potential use of CytoSorb in the setting of intoxications.

Giuntoli et al. recently reported on a case of quetiapine overdose in a 27-year-old healthy woman, admitted to intensive care unit after deliberate quetiapine overdose.¹³ Despite 24 hours of standard treatment including charcoal, diuretics, and laxatives, quetiapine levels remained still very high (1850 μg/L, normal range of 70–170 μg/L) resulting in the initiation of CytoSorb hemoperfusion in combination with continuous renal replacement therapy to accelerate quetiapine elimination. After only 12 hours of combined treatment, the level of quetiapine had already been reduced by 65%, and after 96 hours, she was able to be extubated and eventually discharged to a step-down unit after 7 days.

Another case report by Schroeder et al. described a 19-year-old female who had ingested 18 g of the antidepressant venlafaxine (240 times the daily therapeutic dose) with subsequent development of severe takotsubo cardiomyopathy and multiorgan dysfunction syndrome.¹⁴ As there is minimal clearance of the drug with hemodialysis, while at the same time, there is no specific antidote available, she was treated with intravenous lipid emulsion (ILE) and CytoSorb to increase detoxification of the drug. Extracorporeal life support (ECLS) was commenced as a bridge to support the cardiac failure. Despite the relatively short use of CytoSorb of only 9 hours, there was a substantial reduction in venlafaxine plasma levels and its metabolites under the combined therapy. Over time other therapies including the ECLS, ventilation, and dialysis could be withdrawn and the patient went on to make a full recovery.

In the study from Hassan et al.¹⁵ including 55 consecutive patients undergoing emergency open-heart operations who were at high risk of bleeding due to prior treatment with therapeutic doses of coagulation-active substances (i.e., Ticagrelor or Rivaroxaban), the authors could show a considerable benefit in CytoSorb-treated patients compared with controls in terms of drainage volumes, need for blood transfusions, total operation time, rethoracotomy rate, and retention in the intensive care unit and hospital. According to the authors, these favorable results were directly attributable to the effect of CytoSorb adsorbing both substances which, they note, is the only way currently available in this patient population to increase patient safety and reduce bleeding complications.

In our set of patients, 3 of 4 patients have survived the acute phase followed by a good clinical recovery thereafter. Whether the application of CytoSorb has substantially contributed to the good outcome in the context of this multimodal treatment approach is difficult to confirm and remains speculative. Taking the pathophysiology of post cardiac arrest syndrome and its elevated levels of cytokines into account,¹⁶ CytoSorb, however, might also have had some additional beneficial immunomodulatory properties in these cases next to potential detoxification effects. So Lother et al. were suggesting an additional beneficial effect of cytokine adsorption to VA-ECMO therapy during post-cardiac arrest care in 2 patients who underwent VA-ECMO therapy together with CytoSorb therapy after cardiac arrest.¹⁷ This is further supported by recent results from Calabro et al. in patients with cardiogenic shock undergoing CytoSorb therapy.¹⁸ The presented cases do not allow to make a definite assumption on the direct CytoSorb effect as the presented courses of drugs cannot be reliably distinguished from the natural drug kinetics. On the other hand, the observed decrease under CytoSorb therapy and the resulting clinical effects possibly may have been stronger than what could have been expected by the normal physiologic metabolism. The first case, in particular, shows that a reliable prediction of lowering toxic drug levels with CytoSorb cannot be made, and drug levels have to be monitored closely.

We are well aware of the fact that there is a high variance in the results, which is due to the heterogeneity of patients, applied drugs, timing, and dosing of the devices. Furthermore, as this case series is of purely retrospective and descriptive nature, a control group is missing. Due to this lack of comparability, no clear recommendation can be made based on the results of this case series. However, as there is still a paucity of data concerning potential elimination of beneficial drugs, we recommend that close monitoring of medications and particularly of antibiotics should be performed.

When or to which extent CytoSorb hemoadsorption, overall representing a safe procedure with no confirmed unexpected serious device–related adverse events reported in over 88,000 CytoSorb device treatments worldwide so far, should be considered in patients suffering from cardiac arrest/cardiogenic shock due to drug intoxication cannot be clearly stated at this stage and randomized controlled trials investigating the potential benefit of hemoadsorption in the indication of acute intoxications would be highly desired. Of note, such an approach would be very challenging given the high heterogeneity of intoxicated patients and the overall low amount of specific cases. However, intraoperative use of CytoSorb therapy in infective endocarditis as well as use in eCPR seem to be promising indications based on the underlying pathophysiology and the presence of a relatively well-defined time point for intervention with CytoSorb (i.e., during CPB and with start of ECLS, respectively).^17,19

In summary, CytoSorb was easy to apply in combination with VA-ECMO and CRRT. Based on the reported dramatic decline in drug levels during treatment, that fits in the device’s characteristics, we strongly suggest to further investigate the potentially lifesaving role of CytoSorb therapy in patients with acute intoxications and requiring multiple organ supportive techniques.