Respiratory events with terlipressin and albumin in hepatorenal syndrome: A review and clinical guidance

Abstract

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a serious complication of severe liver disease with a clinically poor prognosis. Supportive care using vasoconstrictors and intravenous albumin are the current mainstays of therapy. Terlipressin is an efficacious vasoconstrictor that has been used for 2 decades as the first-line treatment for HRS-AKI in Europe and has demonstrated greater efficacy in improving renal function compared to placebo and other vasoconstrictors. One of the challenges associated with terlipressin use is monitoring and mitigating serious adverse events, specifically adverse respiratory events, which were noted in a subset of patients in the recently published CONFIRM trial, the largest randomized trial examining terlipressin use for HRS-AKI. In this article, we review terlipressin's pharmacology, hypothesize how its mechanism contributes to the risk of respiratory compromise and propose strategies that will decrease the frequency of these events by rationally selecting patients at lower risk for these events.

1 ∣. INTRODUCTION

Hepatorenal syndrome (HRS) is a devastating complication of advanced liver disease and is associated with high morbidity and mortality.¹ In this manuscript, we will use the most recent terminology of hepatorenal syndrome-acute kidney injury (HRS-AKI) in reference to the acute onset form of this kidney injury, which replaces the prior term ‘HRS type 1’ and has a near synonymous definition.² HRS-AKI is a form of functional renal failure. The pathophysiological hallmarks include circulatory dysfunction, characterized by splanchnic vasodilation resulting in a decrease in effective circulating volume, in combination with intense intrarenal vasoconstriction.³ The definitive treatment for HRS-AKI is liver transplantation; however, this option is not available for all patients. In the absence of liver transplantation, supportive treatments include the use of systemic vasoconstrictors in combination with intravenous (IV) albumin. In concert with albumin, terlipressin is recommended as the first-line vasoconstrictor for the management of HRS-AKI in Europe and Asia, where it is approved for this use.⁴ Terlipressin is a vasopressin analogue, which is metabolized into a pharmacologically active metabolite lysine-vasopressin, which acts predominantly on the V1a receptor in vascular smooth muscle.⁵ Compared to vasopressin or its direct predecessor ornipressin, terlipressin has a longer half-life and more predictable therapeutic window, which allows for bolus administration through a peripheral IV rather than the central catheter.^6,7 While other vasopressors, such as norepinephrine, have shown efficacy in the management of HRS-AKI, these agents are administered by continuous infusion and require intensive care unit (ICU) admission for administration.⁸ Terlipressin has been used outside the ICU safely and effectively for many years in Europe, but it is not currently available in the United States or Canada. In fact, there are no currently approved vasoconstrictor therapies for HRS-AKI in the United States.

Terlipressin has been the focus of three North American randomized trials to treat HRS-AKI.^9-11 In the most recent trial (CONFIRM), terlipressin demonstrated efficacy in a reversal of HRS-AKI compared to albumin infusion alone.¹¹ However, this trial also highlighted the occurrence of respiratory failure with terlipressin (13.5% compared to 5% in placebo-treated patients) associated with the protocolized treatment.¹¹ Our focus is to review the pharmacology of terlipressin, describe the pathophysiology of adverse respiratory events associated with the use of terlipressin and propose strategies that can help reduce the frequency of these adverse events in this difficult-to-treat patient population.

2 ∣. TERLIPRESSIN

Including manuscripts from Europe and Asia, terlipressin has been studied in more than 20 randomized trials and is currently recommended as first-line vasoconstrictor therapy for HRS-AKI by multiple national and international liver society guidelines.^2,4,12-14 As a vasopressin analogue, its mechanism of action addresses the systemic renal hypoperfusion that results from portal hypertension by countering splanchnic vasodilation and, thereby, increasing effective circulating volume.^15-17

The goal of treatment for any patient with HRS-AKI is to reverse AKI, as measured by improvement in serum creatinine, in concert with medical stabilization of concurrent complications of decompensated cirrhosis. Terlipressin has performed similarly or better at reversing HRS-AKI compared to other vasoconstrictors, like norepinephrine or midodrine/octreotide, and is superior to IV albumin therapy alone.^13,14,18,19 Successful treatment with terlipressin has been linked to decreased ICU length of stay, lower rates of renal replacement therapy and less renal dysfunction following liver transplantation.¹¹ The latter point is of particular importance, as better renal function peri-transplant is strongly associated with overall improved short-term surgical outcomes in cirrhosis.²⁰ Reversing HRS-AKI is associated with improved survival both in post hoc analysis of clinical trials and in the real-world setting.^21,22 However, no clinical trial studying terlipressin has demonstrated a statistically significant mortality benefit. This can likely be attributed to a variety of factors. Patients with decompensated cirrhosis are critically ill and have a high expected short-term mortality.²³ As supportive therapy, terlipressin does not reverse underlying liver disease and the competing risks of liver transplant and other complications of cirrhosis likely blunt the positive effects of HRS-AKI reversal in trial settings. In addition, no individual trial studying terlipressin has been designed or adequately powered to detect a mortality signal.

3 ∣. RESPIRATORY ADVERSE EVENTS

When considering therapies that rely on surrogate outcomes like improvement in kidney function in trials, particular attention should be paid to adverse events. In the CONFIRM trial, respiratory failure was reported in 13.5% of patients treated with terlipressin compared to 5% of patients treated with placebo.¹¹ This stark difference was not reported in previous terlipressin trials. Therefore, it is important to understand the physiological events that may lead to the development of these events, including the development of pulmonary oedema, volume overload or other respiratory insults. In the CONFIRM trial, respiratory events were defined by the site investigator and were not defined a priori. Therefore, discussions regarding respiratory events after the use of vasoconstrictors and IV albumin must be considered in general pathophysiological terms.

There are three principal physiological determinants involved in the development of pulmonary oedema that is relevant to terlipressin's mechanism of action. These include (1) hydrostatic pressure, defined as the driving pressure within pulmonary capillaries ‘pushing’ fluid out of the vascular space, (2) oncotic pressure, defined as the pressure contribution of cellular elements and macromolecules that help retain fluid within the vascular space and (3) the permeability of vascular endothelium, which contributes to ease of molecular movements in and out of the vascular space and across the alveolar membranes. This may be described mathematically according to the Starling relationship, where the rate and direction of fluid movement across the vascular endothelium (Q_f) are determined by the influence of the endothelial barrier (K_f) and the driving forces on both sides of the endothelium:

$${\mathrm{Q}}_{{}_{\mathrm{f}}}={\mathrm{K}}_{{}_{\mathrm{f}}}\left(\left[{\mathrm{P}}_{{}_{\text{iv}}}-{\mathrm{P}}_{{}_{\text{ev}}}\right]-\sigma \left[{\pi }_{{}_{\text{iv}}}-{\pi }_{{}_{\text{ev}}}\right]\right).$$

where P_iv represents intravascular hydrostatic pressure, P_ev represents extravascular hydrostatic pressure, σ represents the reflection coefficient and π_iv/π_ev represents the intravascular and extravascular oncotic pressures respectively.²⁴

The use of terlipressin and albumin directly influences the forces described above. Terlipressin directly increases hydrostatic pressure within vessels by (1) shunting blood from the dilated splanchnic vascular beds and into central circulation (increasing cardiac preload), and (2) increasing systemic vascular resistance (increasing cardiac afterload). While IV albumin may increase plasma oncotic pressure thus decreasing fluid movement out of the vascular space, the increase in plasma volume in combination with the effects of increased pre- and afterload likely contributes more to increased hydrostatic pressures (Figure 1).²⁵

FIGURE 1.

Effects of Terlipressin on HRS-AKI Pathophysiology. This illustration depicts the intended mechanism of action of terlipressin (green arrow) and the downstream physiological effects (blue arrows) of terlipressin.

Taking this physiology into account, we can hypothesize that there were several contributing reasons for the adverse respiratory events signal in the CONFIRM trial. First, a larger trial design (N = 300 patients, compared to the next largest terlipressin trial with N = 196 patients) makes it easier to detect these events.¹¹ Second, the albumin dosing strategies in the CONFIRM trial were not specifically controlled in the protocol and relied on weight-based guideline dosing.⁴ In a pooled analysis of the REVERSE and OT-0401 trials, the mean total albumin dose was 225 g for patients treated with terlipressin and 224 g for patients treated with placebo.²⁶ Relative to these previous terlipressin trials, albumin dosing in CONFIRM was higher, with a mean total dose (prior to randomization and during treatment) of 534.4 g for patients treated with terlipressin and 610.2 g for patients treated with placebo during the index hospitalization, a notable increase from these prior studies.^11,26 Third, in CONFIRM, patients with a high model for end-stage liver disease (MELD) scores, high acute-on-chronic liver failure (ACLF) grade or pre-existing multisystem organ dysfunction were determined to be at higher risk for respiratory events and less likely to benefit from terlipressin treatment.²⁷ Albumin amounts of 500–600 g likely exceed the necessary intravascular volume most patients with HRS-AKI require. Current guidelines recommend a maximum initial dose of 1 g/kg with a maximum daily dose of 100 g for initial resuscitation; some experts use the dry weight of these patients, so in some cases, the total dose of albumin may be lower than 100 g. After initial resuscitation, albumin is recommended at 20–40 g/day with vasoconstrictor use; however, further studies are needed to refine optimal dosing recommendations.^2,4,12

In addition to concerns about hydrostatic pulmonary oedema, patients with decompensated cirrhosis are at risk for developing non-hydrostatic pulmonary oedema (NHPE) as seen in other critically ill populations such as patients with acute respiratory distress syndrome.²⁸ Although terlipressin does not contribute mechanistically to the development of NHPE, terlipressin can potentially exacerbate NHPE by increasing the hydrostatic pressure in the capillaries, thereby worsening the alveolar injury.

In sum, we hypothesize that the respiratory events seen in terlipressin-treated patients were likely driven by increased pulmonary oedema in a subpopulation of patients who were at higher risk for respiratory compromise.

4 ∣. MONITORING FOR ADVERSE RESPIRATORY EVENTS

To assess for the potential adverse respiratory event of pulmonary oedema–associated hypoxia, regular pulse oximetry monitoring is likely the simplest and most widely available tool for patients who are being initiated on combination therapy with terlipressin and albumin.

In concert with a detailed history, physical exam and vital sign assessment, serial pulse oximetry assessment is used routinely in the in-patient setting for the detection of hypoxia in patients at risk for pulmonary oedema. In cardiac in-patient units, pulse oximetry provides a very useful monitoring modality for the early detection of pulmonary oedema–associated hypoxia in patients with systolic or diastolic heart dysfunction.²⁹ Since the physiology of terlipressin-associated hypoxia in patients with cirrhosis bears similarities to patients with heart failure, periodic pulse oximetry measurements should be used regularly in this population. Furthermore, since the progression of potential hypoxia owing to hydrostatic pulmonary oedema is typically gradual, serial pulse oximetry monitoring can be invaluable to providers for the early detection and intervention of clinically significant hypoxia (see Management Strategies below). There is little evidence to guide the frequency of pulse oximetry monitoring in any clinical setting including HRS-AKI. Historically, pulse oximetry frequency has largely been left to clinicians' judgement and/or driven by protocols based on overall hospital acuity (general medical ward, telemetry unit or intensive care setting), thus we recommend the same.

In the setting of clinically significant hypoxia as detected by pulse oximetry, chest radiography (chest x-ray) provides an expeditious and practical diagnostic tool to assess for potential aetiologies of hypoxia. Important early chest x-ray findings in the context of hydrostatic pulmonary oedema include interstitial oedema and vascular cephalization. In addition to chest radiography, arterial blood gas analysis can be considered to quantify the degree of hypoxia and guide further management. All patients with HRS-AKI should have a baseline electrocardiogram (±cardiac enzymes) to evaluate for ongoing cardiac ischaemia, which would warrant reconsideration of terlipressin use. Echocardiography should also be considered to screen for systolic, diastolic and valvular dysfunction, which again may inform the choice of therapy.

5 ∣. MANAGEMENT STRATEGIES RELATED TO TERLIPRESSIN USE IN COUNTRIES WITH CURRENT APPROVAL

The most important aspect when considering terlipressin in the setting of HRS-AKI is securing the correct diagnosis.¹² Once the diagnosis is made, patients should be admitted to the hospital, preferably in closely monitored units where treating physicians and nurses have experience with IV vasoconstrictors and decompensated cirrhotic patients. Aside from performing a very detailed physical exam, physicians and nurses should monitor vital signs, urine output, oxygen saturation and perform cardiopulmonary auscultation every 6–8 h. Levels of oxygen saturation deemed appropriate for terlipressin use are context- and patient-dependent; however, SpO₂ < 90% is a reasonable screening tool that would prompt further evaluation and caution. Emphasis should also be placed on the ACLF grade, which is the largest determinant of response to terlipressin and albumin.³⁰ Ancillary assessments mentioned in the preceding section should be performed based on clinical judgement.

In patients with no response or only partial response, terlipressin should be discontinued within 2 weeks. Since treatment with terlipressin is performed with IV albumin (20–40 g/day per guideline recommendations), albumin should be infused at a rate of approximately 10 g/h to avoid precipitating pulmonary oedema (expert opinion, not evidence-based).² If patients require oxygen supplementation and volume overload/pulmonary oedema is suspected, terlipressin should be discontinued. Proactive and careful titration of albumin combined with consistent, periodic monitoring of oxygen saturation may help mitigate the risks of adverse respiratory events in patients with HRS-AKI being treated with vasoconstrictor therapy. Our expert opinion, represented in Table 1, is consistent with the approach described for treatment with terlipressin in Europe.

TABLE 1.

Clinician recommendations

1. Baseline assessment	Before starting terlipressin, a detailed history, physical exam, and vital sign assessment must be completed, with particular attention to ACLF grade, pulse oximetry, chest x-ray, TTE (if indicated), and volume status. Terlipressin should only be initiated if: Patient has a clear indication for therapy Risk/benefit ratio favours initiation Patient lacks risk factors for worsening respiratory status (ACLF grade 3, pulse oximetry <90%, abnormal ejection fraction on TTE, pulmonary edema on CXR)
2. Ongoing assessment	If the patient is treated with terlipressin, regularly monitor pulse oximetry and volume status. If the patient: has stable respiratory function and volume status, continue terlipressin demonstrates worsening hypoxia, consider stopping or holding terlipressin
3. Stop terlipressin	Stop terlipressin if SCr is <1.5 mg/dl for 2 consecutive tests or within 0.3 mg/dl of baseline (treatment success) SCr is at or above pre-treatment value 72 h after initiating terlipressin (treatment failure) Patient has been on treatment for 2 weeks (maximum recommended treatment course) Patient experiences serious adverse events, including respiratory compromise

Abbreviations: ACLF, acute-on-chronic liver failure; CXR, chest x-ray; SCr, serum creatinine; TTE, transthoracic echocardiogram.

6 ∣. AREAS FOR FUTURE RESEARCH

Research aimed at mitigating respiratory distress in patients with HRS-AKI treated with terlipressin should focus on two areas: (1) validating a rigorous and practical monitoring algorithm for hypoxia and volume overload during HRS-AKI therapy and (2) continuing to study optimal albumin dosing and administration.¹⁰

As mentioned above, attentive pulse oximetry monitoring should serve as the first step in screening for the development of respiratory insufficiency. Owing to the challenges with assessing intravascular volume status in this population, real-time objective measures of venous filling pressures may be useful to guide volume resuscitation. There is growing interest in the application of point-of-care ultrasound (POCUS) to cardiovascular and lung imaging, which may provide additional important monitoring strategies in the near future.³¹ Intravenous albumin dosing should be evaluated and proceed in parallel with ongoing research around terlipressin use. Guideline dosing for IV albumin has been unchanged for decades and is largely based on small studies and expert opinion.³² No clear stopping rules exist to guide clinicians as to when to reduce or complete albumin infusions while concurrently administering terlipressin. Serum albumin is ‘not’ a marker of volume status and transfusion to a prespecified serum albumin threshold is associated with increased rates of respiratory events and, therefore, should not be used as part of HRS-AKI management.³³ It may be that objective measures of intravascular volume are best to determine proper albumin dosing, but more work is needed in this area.

Further study is also needed around dosing strategies and patient selection for terlipressin. In initial European studies, terlipressin was administered with repeated IV boluses (starting dose of 0.5–1 mg every 4–6 h, and increasing to a maximum of 2 mg every 4–6 h).³⁴ Although this approach is most common, a randomized trial compared the efficacy and safety of terlipressin given by continuous IV infusion (dose 2 mg/day up to 12 mg/day) against IV boluses and showed similar response rates between both groups, demonstrating that the mean effective dose of terlipressin was lower in the continuous infusion group and was associated with a lower rate of adverse events.³⁵ In this dosing strategy, the dose is usually increased in a stepwise manner if serum creatinine does not decrease by at least 25% with respect to the pre-treatment value after 72 h of treatment. Continuous IV infusion of terlipressin can be considered in patients at high risk for adverse events; however, this approach requires further research.³⁵ When considering the evolving patient population of decompensated cirrhosis and the increasing incidence of concurrent non-alcoholic fatty liver disease, diabetes and chronic kidney disease (CKD), less is known about terlipressin response rates in patients with ‘pure’ HRS-AKI compared to patients with HRS-AKI superimposed on CKD related to diabetic nephropathy, for example. Overall, creating a national registry to quantify adverse events and response rates to terlipressin could help advance research in both of these areas. In addition, continued work to identify biomarkers that predict adverse events and responses will be important for optimizing safety and outcomes.^36,37

7 ∣. CONCLUSION

Terlipressin can be a safe and effective treatment for the reversal of HRS-AKI when applied to a carefully selected patient population in a closely monitored setting. One main safety concern when treating patients concurrently with terlipressin and IV albumin is the potential development of respiratory failure, which is likely multifactorial. We hypothesize that this is largely driven by hydrostatic pulmonary oedema from increased pulmonary vascular pressures, with the potential additive effect of a pulmonary capillary leak–induced non-hydrostatic pulmonary oedema in a subgroup of patients with higher acuity and multisystem organ dysfunction (e.g. ACLF grade 3). Fortunately, the pathophysiology of hydrostatic pulmonary oedema does not seem to be idiosyncratic but rather develops somewhat predictably and gradually. We therefore suggest an algorithm for monitoring this patient population using regular pulse oximetry for early detection of hypoxia, close monitoring of clinical volume exam and urine output and regular adjustments to terlipressin and albumin based on the evolution of the patient's clinical status. In addition, the pre-treatment screening of patients for any active infectious process can help decrease the risk of non-hydrostatic acute lung injury. For a majority of patients with HRS-AKI, terlipressin represents the best chance of restoration of renal function and has an appropriate safety profile. However, patients who are at risk or develop early signs of hypoxia should have their terlipressin and albumin doses held. Further research aimed at more objective measures of volume status and more personalized albumin dosing is needed.

Key points.

• Hepatorenal syndrome-acute kidney injury (HRS-AKI) is a severe complication of advanced liver disease.

• Terlipressin can be a safe and effective treatment for the reversal of HRS-AKI when applied to a thoughtfully selected patient population in a closely monitored setting.

• One main safety concern when treating patients concurrently with terlipressin and IV albumin is the potential development of respiratory compromise.

• Understanding the pathophysiology for the development of respiratory failure and applying a consistent algorithm for patient selection and safety monitoring are important to optimize outcomes in HRS-AKI.

Abbreviations:

HRS

hepatorenal syndrome

AKI

acute kidney injury

IV

intravenous

ICU

intensive care unit

MELD

model for end-stage liver disease

ACLF

acute-on-chronic liver failure

NHPE

non-hydrostatic pulmonary oedema

CKD

chronic kidney disease

POCUS

point-of-care ultrasound

CXR

chest x-ray

SCr

serum creatinine

TTE

transthoracic echocardiogram

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analysed in this study.