Connection of the RRT machine to the ECMO circuit.
The RRT circuit may need to be reconfigured slightly to take account of access and return vascular pressures, as the machine safety mechanisms may not allow the use of high-pressure systems. Connection and disconnection from the ECMO circuit increases the risk of air entrainment, leakage and infection. It is important to remember that air can be entrained in the ECMO circuit from any indwelling vascular line open to the air. Connection of the RRT device to the ECMO venous circuit (Figure 12.1) allows the use of all the potential modes including continuous veno-venous haemofiltration, continuous veno-venous haemodialysis and continuous veno-venous haemodiafiltration. Connecting the return blood from the continuous RRT device to the tubing before the oxygenator allows air and thrombi to be trapped in the oxygenator, and avoids venous admixture into the oxygenated tubing of the ECMO circuit. Connecting a full RRT system allows accurate monitoring of any mode of filtration, increases the accuracy of fluid balance and keeps a constant blood flow through the filter. Finally, filters can easily be changed without disruption of the ECMO flow.
Renal replacement therapy can be performed by connecting the RRT device to the venous line before the centrifugal pump, but this low negative pressure increases the risk of haemolysis and microembolization. Air embolism is more likely to happen at the time of connection/disconnection.
Independent vascular access can be used. The advantages of this approach include less interference with the ECMO circuit. The insertion of a large catheter in an anticoagulated patient increases the risk of bleeding. Veins may already be in use with other lines. It is important that impaired cerebral venous return is considered in patients with large catheters inserted in all neck vessels. The RRT circuit and vascular catheters can be a source of major air embolism, even when not directly connected to the ECMO circuit.
Anticoagulation with RRT and ECMO
The anticoagulation used in patients with ECMO is sufficient to prevent thrombi forming in the RRT circuit. Additional anticoagulation is not routinely used.
If ECMO support is provided without systemic anticoagulation, the RRT circuit is at high risk of occlusion with thrombi (the blood flow through an RRT circuit is much lower than in the ECMO circuit). Techniques reliant on the anticoagulant running exclusively in the RRT circuits are possible (such as citrate anticoagulation).
Plasmapheresis
Plasmapheresis can easily be conducted during ECMO by using a compatible RRT machine and connecting it to the ECMO circuit as described above.
Sepsis on ECMO
ECMO during refractory septic shock
Septic shock in the adult patient is usually associated with low systemic vascular resistance and refractory hypotension with preserved cardiac output. This distributive shock is related to a maldistribution of blood flow at a microvascular level, and veno-arterial ECMO is of little value in restoring vascular tone.
This is different from what is observed in children, and the international guidelines for the management of severe sepsis and septic shock in children recommends considering veno-arterial ECMO for circulatory collapse unresponsive to all conventional treatment. This remains controversial in adult patients suffering from refractory septic shock. Veno-arterial ECMO might prove useful if the cause of the shock is cardiogenic in addition to distributive.
Nosocomial infections in patients supported with ECMO
There is a long definition of nosocomial infection in patients supported with ECMO: an infection not present at the start of support but detected more than 24 h after ECMO commencement, or within the first 48 h after ECMO discontinuation, and with a pathogen different from those detected within 7 days before ECMO initiation.
The risk of infection is markedly increased in the patient supported with ECMO because of the presence of multiple indwelling devices. Activation of the inflammatory response by the ECMO circuit, coupled with the primary insult, often leads to a relatively immunosuppressed status that may decrease the ability to respond to secondary insults.
Nosocomial infection is the second most common complication of ECMO after haemorrhage, and affects up to two-thirds of patients supported by ECMO. Ventilator-associated pneumonia and bloodstream infections are the most common causes, followed by surgical wounds, urinary tract infection and cannulation-related infection.
The most commonly identified organisms include coagulase-negative Staphylococcus, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans. Enterobacter, Klebsiella, Enterococcus and Escherichia coli species are also possible.
The risk of nosocomial infection is increased if the ECMO support is continued for a long time, in cases of mechanical complication, if the patient has an autoimmune disease and if veno-venous ECMO is used.
All the standard measures used in intensive care to decrease the risk of nosocomial infections are applicable. Elevation of the head of the bed, oral prophylaxis and medical treatment of reflux should be strictly followed. All unnecessary lines should be removed. Strict aseptic techniques should be used to access all indwelling catheters.
The diagnosis of newly acquired infection can be challenging because of the intense inflammatory response that mimics sepsis itself. The temperature of the blood is maintained by the circuit’s heat exchanger, and fever can easily be masked. Physical examination and radiographic changes may be difficult to interpret. Subtle changes in clinical condition and signs of poor perfusion manifested by metabolic acidosis, increasing lactate levels, decreasing urine output and a rise in hepatic transaminases are all indices of possible sepsis.
Blood, urine and tracheal cultures should be obtained from patients on ECMO at the earliest suspicion of a possible secondary infection.
Antibiotic therapy
The principles of good antibiotic stewardship apply to all critically ill patients, and include appropriate initial therapy, regular reviews, de-escalation where possible, appropriate prophylaxis, and use of local guidelines and specialist advice.
Treatment of documented infections should follow the same principles as for patients who are not on ECMO support. The increased volume of distribution and impaired drug clearance may affect the dosage of antibiotics. Drug level monitoring in the blood is appropriate where possible.
The underlying diagnosis in the majority of patients who receive ECMO for severe acute respiratory failure is bacterial or viral pneumonia, although a definitive microbiological diagnosis is not reached in approximately one-third of patients. Antibiotic therapy for severe pneumonia should initially be broad spectrum and then more focused when a definitive microbiological diagnosis is reached. National and local patterns of disease and antimicrobial resistance will guide initial and subsequent therapy, and local advice should be sought.
It is common practice to administer single-dose prophylactic antibiotics on ECMO cannulation, decannulation and when changing components of the ECMO circuit, although there is limited evidence to support this.
Pharmacology and ECMO
Effective treatment of the primary disease and subsequent complications is required in order to cure those patients supported with ECMO.
Drug pharmacokinetics may be altered in patients on ECMO because of an increased volume of distribution and reduced drug clearance, due at least in part to the binding of drugs to the ECMO circuit (Figure 12.2).
Pharmacokinetic changes of drugs during ECMO.
It is not possible to predict the effect of ECMO on pharmacokinetics, and it is impossible to integrate this with the effects of critical illness, drug interactions and RRT.
Therapeutic drug monitoring helps prevent toxicity and monitor efficacy.
Intravenous drugs should be administered directly to the patient and not via the ECMO circuit. This reduces the risks of air entrainment during manipulation of the connectors, or inadvertent rapid drug delivery due to negative pressure in the drainage limb of the circuit. Clotting factors and lipid-rich solutions, such as propofol and parenteral nutrition, should not be given directly in the ECMO circuit, as the high concentration of lipids may block the oxygenator.
Drug availability changes during ECMO
The ECMO circuit will increase the volume of distribution because its material can bind circulating proteins and drugs. This will be affected by the type of components used in the circuit. Reduced adsorption is observed in hollow-fibre oxygenator membranes. Less adsorption is observed in circuits with shorter tubing and those using centrifugal pumps. Drug molecular size, degree of ionization, lipophilicity and plasma protein binding may also influence the adsorption to circuit components.
Adsorption of lipophilic drugs to ECMO membranes and tubing is common and likely to rapidly reduce plasma concentrations. Highly lipophilic drugs such as fentanyl or midazolam will disappear almost completely in an ECMO circuit. However, not all drugs are affected, and the extent of sequestration is not consistent.
The volume of the ECMO circuit increases the total blood volume, and this is compounded by the haemodilution due to repeated blood transfusions, loss in the circulating blood volume during changes in the equipment and the administration of fluids to maintain ECMO flow. This will mainly affect hydrophilic drugs.
The inflammatory response induced by the exposure of blood to foreign material and sepsis causes a redistribution of albumin that is disproportionate, resulting in a low plasma albumin concentration. The proportion of unbound drugs is then increased, with a higher extravascular distribution.
Prolonged elimination is multifactorial, but the reduction of renal function is the primary determinant. Prolonged half-lives of gentamicin and vancomycin are seen in ECMO patients, and meropenem will often remain at a higher level. Adding haemofiltration or other modes of continuous RRT to the ECMO device may increase drug clearance, but this is disputed.
Regional blood flow changes in the liver during pulseless veno-arterial ECMO can also affect clearance of those drugs with a high extraction ratio, such as propranolol.
A decreased drug elimination rate predisposes patients to toxicity, especially for the drugs with a narrow therapeutic window.
Available pharmacokinetic studies have many limitations because they have been performed ex vivo and in neonates with immature enzymatic and elimination systems.
A summary of the changes in pharmacokinetic caused by the ECMO circuit is shown in Table 12.2.
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