EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Traditionally, a period of mechanical ventilation (MV) in the intensive care unit (ICU) after orthotopic liver transplant (OLT) has been considered a standard of care, despite a decline in routine MV after major surgery.¹ Over the past 3 decades, numerous studies have demonstrated the feasibility and safety of early liberation from MV after OLT, in both adult and pediatric patients, when the individual patient is deemed appropriate for such treatment, often as part of fast-track surgery.^2-10

There is some debate as to whether early extubation should be defined as immediate extubation at the end of surgery or as extubation within 4 to 8 hours after surgery, with the suggestion that immediate postsurgery extubation may have a lower incidence rate for adverse events versus the rate associated with invasive ventilation for longer periods, eg, up to 6 to 9 hours postoperatively.^5,6,11,12 However, although early extubation has been established as feasible and safe, questions remain with regard to specific outcome benefits that may foster the perception of fast-track extubation as necessary or desirable.¹³

The rationale for not undertaking early extubation includes, among other things, preemption of some known early postoperative pulmonary complications, diaphragmatic dysfunction, respiratory insufficiency secondary to pain, and the deleterious effects of unique lung-liver pathologies (eg, hepatopulmonary syndrome). Other potential concerns include hemod-ynamic instability, as well as major metabolic abnormalities, related to massive blood product transfusion, renal dysfunction, and the inherent nature of liver surgery.^13,14 Furthermore, liver transplant patients are susceptible to neurological complications of their disease, which may necessitate prolonged duration airway protection.¹⁴ These potential complications are known to occur in patients with various preoperative physiological conditions and may coincide with other surgical complications of this major procedure.¹⁵

In contrast, the rationale for early extubation includes a desire to avoid the generic risks of ongoing MV, such as muscle deconditioning, ventilator-associated pneumonia, and increased mortality, as well as other specific complications.¹⁶ The theoretical effect of positive-pressure ventilation on hepatic function, as well as the improvement with spontaneous ventilation, is well described in the literature, although the effect on graft function has not been clearly established.^17,18 One systematic review and meta-analysis has sug-gested a lower incidence of graft dysfunction for patients managed with early extubation compared with patients who received standard care (0.3% vs 3.8%, respectively; P < .01).¹⁹ Certainly, prolonged MV (>96 hours) is associated with a significant reduction in patient and graft survival, but this relationship will be impacted by the underlying complexity of those patients requiring prolonged MV and not a function of a simple linear association between MV duration and outcome.²⁰ Furthermore, there are probable institutional benefits associated with early extubation versus conventional treatment.^13,21

Bhatia and colleagues have recently explored the association of early extubation after OLT with postoperative vasopressor use and acute kidney injury.²² They reported a shorter duration of vasopressor requirement (0 vs 2 days, respectively; P < .01) and less need for renal replacement therapy (3% vs 21.2%, respectively; P = .05) in patients who received fast-track extubation (defined as extubation within 4 hours after the end of surgery) compared with patients who received conventional treatment. Acute kidney injury and renal replacement therapy requirement after OLT are associated with increased mortality, liver graft failure, and development of chronic kidney disease.²³ As such, Bhatia and colleagues have earned commendation for their exploration of the association of postoperative MV and outcomes beyond those purely associated with respiratory or primary graft complications.

Patient-centered outcomes with regard to fast-track policies, including those associated with ventilatory management, are worthy of further study. Scoring systems may be useful to identify suitable patients for fast-track programs and particularly for early extubation after OLT.^1,24 Similarly, another proposed area of focus in pediatric patients is the identification of the risk factors for requirement of prolonged MV after OLT.²⁵ Identification of these patients and the relevant underlying factors is crucial to facilitate successful mitigation of the risks associated with prolonged MV. Another worthy point of concern is the negative effect of extubation failure and the requirement for reintubation, which is a predictor of poor outcomes, including lower respiratory tract infection, increased ICU length of stay, and mortality.^26-28 A notable single-center study has suggested a stronger association with the risk of death for requirement for reintubation versus duration of MV, although the details of this comparison are complex and warrant further study.²⁹

Within the context of a recent liver transplant, extubation failure represents a hazardous period for patient and graft. The subsequent hypoxemia can impede the oxygen delivery to the graft, which may be exacerbated by apnea during reintubation or by poor graft perfusion during any hemodynamic instability associated with induction of anesthesia. Furthermore, overzealous manual ventilation during an emergency reintubation may have a negative effect on graft perfusion.

There is marked variation in rates of reintubation in studies of fast-track extubation after OLT in adult patients. Rates of reintubation are as high as 15% for patients extubated within 8 hours of the end of surgery, similar to the typical expectation in the setting of a general ICU.^5,30,31 Studies have reported a higher rate of required reintubation for patients extubated after 24 hours versus patients extubated within 24 hours, suggesting that reintubation requirements most often are associated with the original duration of MV and are a function of the complex postoperative factors that have mandated prolonged MV.^3,4,13,32 Although less extensive than for broader population studies, the published data specific to the pediatric population suggest no increased rate of reintubation after early initial extubation.^8,9 An optimal failure rate balances the potential gains of early liberation from MV versus the risks of doing so when, retrospectively at least, early extubation is not appropriate. Furthermore, an important goal is to establish a balance to benefit both the patient and the institution.³³ A proposed optimal failure rate of 5% to 10% has been suggested to accommodate these varying concerns.²⁶

Central to finding this balance is a clear understanding of the potential gains of early extubation. One retrospective comparative single-center cohort study demonstrated that enhanced recovery patients were extubated an average of 6 hours earlier than conventionally treated patients. Although the fast-track group did have lower rates of postoperative pulmonary complications, as well as reduced ICU lengths of stay, many patients in the conventional group would still meet many clinicians’ definition of early extubation.³⁴ Similar differences in duration of MV have been shown in other groups, with similar reductions in length of stay and no differences in postoperative respiratory infections.^35,36 Similar benefits with regard to length of stay, hemodynamic stability, transfusion rates, and infective complications have been reported in pediatric studies.^9,10 Future studies similar to those of Bhatia and colleagues may reveal potential benefits of this approach, particularly those benefits that extend beyond pulmonary complications and length of stay, including important areas such as renal dysfunction.²²

Studies that examine broader patient outcomes and that include the impact on other major organ complications, and not merely focusing on graft or respiratory dysfunction, are important to fully evaluating the role of early extubation after OLT. One recent meta-analysis of 15 studies in adult patients reported only 1 prospective study, and future research may increase this number.¹⁹ While efforts continue to identify those patients who are appropriate candidates for early extubation and other enhanced recovery procedures, it is important to consider likely specific benefits, for both patient and system, as well as any potential harms. This will enable the decisions regarding this element of care to be both evidence based and more specific to patients and disease. Additional high-quality evidence is required for both adult and pediatric liver transplant patients to enhance the notably few data reported for randomized controlled trials in this area. However, in the context of much of the recent work, these answers are perhaps more likely than ever to arrive soon, and future findings are eagerly anticipated.

Volume: 20 Issue: 1 January 2022

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