Key words : Critical care, Diastolic perfusion pressure, Intensive care unit

Introduction

Orthotopic liver transplant (OLT) is a universally accepted treatment for patients who have life-threatening chronic and acute liver disease.^1,2 During the immediate postoperative period after OLT, patients have a high risk of developing acute kidney injury (AKI),^3-5 accounting for an over 60% incidence in some reports.^4,6

Acute kidney injury is a complex syndrome characterized by a deterioration of renal function⁷ and is considered an important risk factor for short-term morbidity.^8,9 Prolonged mechanical ventilation, increased risk of infections, and longer intensive care unit (ICU) stays have been associated with AKI. Moreover, AKI has been related to long-term morbidity, with increased 30-day and 1-year mortality rates.^9-11

A wide variety of risk factors can lead to the development of AKI after OLT, including extended cava cross-clamping time, ischemic renal tubular necrosis, and the use of nephrotoxic drugs. In addition, severe liver disease, such as hepatitis-associated glomerulonephritis, alcoholic liver disease, and related immunoglobulin A kidney disease, can affect the kidneys.^4,12

Blood pressure (BP) is an important determinant of renal perfusion. Therefore, achieving optimal BP in OLT recipients is considered crucial to the prevention of AKI progression.¹⁰ The optimal mean arterial pressure (MAP) target remains under discussion. International consensus guidelines recommend adjusting BP targets according to premorbid BP.¹³ There are limited studies investigating the alleged benefits of adjusting BP targets according to premorbid levels in the clinical setting. The BP deficit relative to the patient’s baseline BP preillness is referred to as relative hypotension.¹⁴

A multicenter randomized controlled trial showed no significant difference in mortality in patients with septic shock and undergoing resuscitation, with a MAP target of either 80 to 85 mm Hg (high-target group) or 65 to 70 mm Hg (low-target group). However, results of this trial also revealed that patients with chronic hypertension in the high-target group had a lower incidence of AKI or requirement for renal replacement therapy.¹⁵ An observational cohort study also investigated differences between premorbid and within-ICU hemodynamic pressure-related parameters in vasopressor-dependent patients who had undergone cardiovascular surgery. Patients with AKI progression had greater pressure deficits than those without AKI progression.¹⁶

In a recent review, including mostly single-center retrospective studies, an association between relative hypotension and adverse outcomes was suggested.¹⁷ More recently, in a multicenter prospective cohort study of ICU patients with shock, the existence of a significant degree of relative hypotension was shown to be associated with an increased risk of AKI.¹⁴

The fact that hypotension is the most prevalent clinical complication in the early postoperative period infers that hemodynamic management is a cornerstones of care after OLT.¹⁸ Other factors, such as persistent cirrhotic hemodynamic status, hypovolemia, or systemic inflammatory response leading to a distributive pattern (characterized by high cardiac output and hypotension due to low vascular systemic resistances), contribute to the fall in BP during the first 24 hours after OLT.¹⁹

These previous finding led us to hypothesize that differences between premorbid and achieved hemodynamic parameters could be associated with the development of AKI in the early postoperative period after OLT.

Materials and Methods

Setting
We conducted a prospective observational study in a 17-bed medical and surgical ICU at a third-level university hospital (Madrid, Spain). The local Ethics Committee (Comité Ético de Investigación Clínica, Instituto de Investigación Hospital 12 de Octubre; Reference CEIC 14/149) approved the study and waived formal review and consent.

Patients
This study included all adult patients (>18 years of age) who underwent OLT between January 2015 to November 2018. Patients undergoing multivisceral transplant and those who died intraoperatively were excluded from the study.

Transplant technique
The surgical interventions were performed using previously described techniques.^20-22 Our study group received transplants from donors after brain death and donors after cardiac death. Recipient hepatectomy was performed without venous-venous bypass, using the vena cava-sparing technique (piggyback), and University of Wisconsin solution was routinely used for graft preservation. A liver graft biopsy before cold perfusion was routinely carried out. Donor grafts were discarded when presenting fibrosis, >30% macrosteatosis, or when the time periods established in the institution protocol were exceeded.

In most cases, biliary reconstruction was carried out by an end-to-end choledochocholedochostomy without a T tube. The liver graft was reperfused off the portal vein after completion of anastomoses of hepatic and portal veins. Hepatic artery anastomosis followed the reperfusion.

Cold ischemia time (CIT) started with donor cross clamping and ended with the removal of the liver from the cold preservative solution before implantation. Warm ischemia time (WIT) began when the liver was taken out of the cold preservative solution for preparation for implantation and finalization with portal reperfusion.

Short-term management
After transplant, all patients were admitted to the ICU. Close management was ensured by board-certified intensivists with 24-hour coverage, according to our institution’s protocol.

The immunosuppressive regimen included tacrolimus and steroids. When renal dysfunction or adverse events related to tacrolimus (nephrotoxicity, hypertension, and diabetes) were evident, we decreased the doses of tacrolimus and added mycophenolate mofetil to the immunosuppressive regimen.

Study protocol
We collected the following intraoperative data: type of graft, donor age, ischemia time, operative times, and transfusion rates. We also collected demographic variables, and severity scores (Acute Physiologic and Chronic Health Evaluation [APACHE II] score and Simplified Acute Physiologic Score 2 [SAPS-2]), which had been documented on ICU admission. We also obtained information on lengths of hospital and ICU stay, as well as the type and grade of surgical or medical complications. Patients had follow-up during the first year after OLT.

Premorbid baseline BP was defined as the mean of the 3 recent values. Mean arterial pressure was estimated from systolic arterial pressure (SAP) and diastolic arterial pressure (DAP) as follows: DAP + (SAP - DAP)/3. Intraoperatively, an arterial catheter was placed in the radial artery, and a pulmonary artery catheter was inserted via the jugular vein.

Premorbid baseline central venous pressure (CVP) was the first value obtained after insertion of the pulmonary artery catheter. Premorbid baseline diastolic perfusion pressure (DPP) and mean perfusion pressure (MPP) were calculated from premorbid baseline DAP and MAP and recorded CVP values as follows: DPP = DAP – CVP and MPP = MAP - CVP.

Time 0 was established the moment the patient arrived at the ICU. Information on hemodynamic results (recorded at 6, 12, 24, and 48 h post-OLT), vasopressor and inotropic medication doses, respiratory parameters, and fluid infusion were documented from time 0 to 72 hours after OLT.

We derived time-weighted average (TWA) values from collected data for each patient. We calculated TWA as follows¹⁶: TWA = (t1X1 + t2X2 + … tnXn)/(t1 + t2 + …+ tn), where Xn is the value of the variable of interest during the nth interval and tn is the duration of the nth interval.

The percent deficit in TWA parameters in relation to baseline parameters was determined as percent parameter deficit. For example, we calculated the percent MPP deficit as follows: (achieved MPP minus baseline MPP)/baseline MPP.

We used the Kidney Disease: Improving Global Outcomes (KDIGO) creatinine and urine output criteria for staging and definition of AKI.²³ Changes in serum creatinine were compared with the premorbid creatinine level, which was defined as the last value before OLT. We assessed KDIGO stage changes from time 0 during the initial 72 hours. We defined an increase of ≥1 KDIGO stage from time 0 as AKI progression (AKI+) and no KDIGO stage change as no AKI progression (AKI-).

Data collection and statistical analyses
Data were prospectively collected in a specifically designed database, allowing blinded data collection. We compared hemodynamic parameters and other variables between the AKI+ group and the AKI+ group.

Qualitative variables are presented as absolute frequency and the corresponding relative percen-tages and were compared using the chi-square test or the Fisher exact test. Quantitative variables are presented as the median and the corresponding interquartile ranges and were compared using the Mann-Whitney U test.

P < .05 (2-sided) was considered significant. A commercially available statistical package (SPSS version 25.0; IBM Corp) was used for all statistical analyses.

Results

From January 2015 to November 2018, 2584 consecutive adult patients were admitted to our ICU. During this period, 182 patients received an OLT and 150 met the study inclusion criteria (Figure 1). Table 1 lists demographic and clinical characteristics of these patients. Of 150 OLT recipients, 88 (59%) had an increase of ≥1 KDIGO stage from time 0 to 72 hours (comprising the AKI+ group). According to KDIGO criteria, 20 patients (23%) were classified as stage 1, 15 (17%) as stage 2, and 52 (59%) as stage 3. Fifty-one patients required renal replacement therapy. We found that the AKI+ group had significantly higher APACHE II, SAPS 2, and Model for End-Stage Liver Disease (MELD) scores.

The intraoperative variables according to their AKI group are shown in Table 2. Both CIT and WIT, as well as packed red blood cells transfusion, were significantly greater in the AKI+ group than in the AKI+ group.

Data on outcomes are shown in Table 3. With regard to clinical outcomes, median ICU stay was 5 days in the full cohort, with a significantly higher ICU and hospital stay in the AKI+ group. In the total group, ICU mortality, hospital mortality, and 1-year mortality were 6.7%, 8%, and 12.7%, respectively. Mortality was significantly associated with AKI development, and AKI was also associated with longer mechanical ventilation time (defined as >24 h) and the diagnosis of nosocomial infection. Early allograft dysfunction incidence was significantly higher in patients experiencing AKI (P < .001), although no impact on long-time graft survival was found.

The comparison of all hemodynamic parameters (including vasopressor doses) at baseline, 6, 12, 24, and 48 hours are listed in Table 4. Baseline perfusion pressures were similar in the AKI+ and AKI- groups. Regarding deficits in BP measurements between the AKI+ group and the AKI- group, %MAP deficit, %SAP deficit, %DAP deficit, and %MPP deficit did not differ between the 2 groups during the initial 72 hours. Similar results were obtained when we compared the cardiac index at each stage.

In contrast, we found that the %DPP deficit was significantly greater in the AKI+ group than in the AKI- group at 12 hours (-8.33% vs +1.93%; P = .037) and 24 hours (-7.38% vs +5.11%; P = .029). At 48 hours, there was no significant difference between the 2 groups, although there was a tendency to have a higher %DPP deficit in the AKI+ group (-4.54% vs +3.36%; P = .07). There was also a significant increase in CVP in the AKI+ group at 24 hours (46.13% vs 15%; P = .043) and 48 hours (40% vs 20.87%; P = .039) regardless of net fluid balance at the end of the period (1420.5 vs 1117.5 mL; P = .238) (Figure 2). There was a slight increase in both dose and time under vasopressor medication in the AKI+ group.

Discussion

In this single-center, prospective, observational study among critically ill patients who received an OLT, we found that the degrees of difference between premorbid and posttransplant DPP and CVP were associated with the development of AKI in the early postoperative period.

There is no doubt that AKI is a frequent complication after an OLT, with an incidence that frequently exceeds 50%.^3,24,25 The true incidence is unknown, as heterogeneous definitions of AKI have been applied. The KDIGO criteria represent a consensus definition of AKI for critically ill patients based on creatinine, urine output, and the need for renal replacement therapies.²² In our population, based on KDIGO criteria, 55% of the patients displayed AKI in the early postoperative period, a rate close to what Hilmi and colleagues concluded.¹² Our rate of renal replacement was as high as 34%, although similar to previous studies.

Determining the risk factors for AHI has significant implications for clinical management and outcomes. Our study revealed an association between AKI after an OLT and higher MELD score and previous chronic kidney disease. Both are classical pretransplant risk factors related to the development of post-OLT AKI in the majority of the studies.^25,26 However, we did not observe this association with other frequent conditions related to AKI, including older age, obesity, fulminant liver failure, or donation after circulatory death.³

Ischemia-reperfusion injury, which compromises the molecular pathways of blood return to the liver after a period of ischemia, is considered one of the cornerstones of liver and kidney physiopathology after an OLT.²⁷ Factors classically related to ischemia-reperfusion injury are longer CIT and WIT and blood transfusion during surgery.⁸ These factors were also associated with the development of AKI in our study and may explain the relationship in our population between AKI and early allograft liver dysfunction, which is concordant to previously published data.²⁸ However, AKI did not involve an increase in graft failure or need for retransplant.

Furthermore, AKI was associated with more respiratory complications, a higher infection rate, a longer hospital and ICU stay, and increased ICU, hospital, and 1-year mortality rates. These results, similar to previous studies,¹⁰ provide evidence that AKI is a potentially severe complication for OLT patients and has significant effects on both short-term and long-term clinical outcomes.

Blood pressure has been considered essential for renal perfusion; hence, MAP is generally used as a goal of care during clinical management. However, the evidence surrounding MAP as a surrogate for organ perfusion is scarce. A large clinical trial involving patients with sepsis failed to prove the association between targeting MAPs of either 65 to 70 mm Hg or 80 to 85 mm Hg and mortality.¹⁵ Nevertheless, in a predefined subgroup analysis of patients with chronic hypertension, targeting a higher MAP was associated with a lower renal replacement therapy requirement.

Recently, perfusion pressure has emerged as the main target in the context of preventing AKI. With low renal vascular resistance, indicated by positive diastolic blood flow velocity, DPP could be a determinant in renal perfusion.^29,30 The reduction in diastolic flow may result from a decrease in DPP, related to an increase in renal venous back pressure and/or a decline in DAP.³¹ Critically ill patients have a narrow pressure autoregulation range; an elevated CVP causes lowering of renal blood pressure below the kidney autoregulation threshold, resulting in pressure-dependent renal perfusion.³²

Different observational studies have revealed that lower DAP and higher CVP were associated with septic AKI, while MAP was not.^33,34 Furthermore, a recent study of patients after cardiac surgery showed an association between decreased DAP, MPP, and DPP but not MAP and AKI. The decreased DPP was caused by elevation of CVP in 23.8% of the patients and by decreased DAP in 76.2% of the patients.¹⁶

To our knowledge, there are no previous studies evaluating the effect of changes from the premorbid BP level on subsequent AKI development or progression after an OLT. We observed a greater DPP deficit in our AKI+ population at 12 hours (-8.33% vs 1.93%; P = .037) and 24 hours (-7.38% vs 5.11%; P = .002). There was also an increase in CVP in the AKI+ group at 24 hours (46.13% vs 15%; P = .043) and 48 hours (40% vs 20.87%; = .039). No differences were found in the other perfusion pressures or cardiac index. These results suggest that both diastolic perfusion and venous congestion play a role in physiopathology of AKI in the early postoperative period after an OLT. Therefore, increasing diastolic blood pressure and/or decreasing renal afterload (CVP) may be considered as a target for hemodynamic management for prevention of AKI development or progression.

Our study had limitations. First, it is a single-center, observational study, conducted on a small sample size. We are aware that further studies involving greater populations and numerous surgical centers are needed to confirm results. An electronic database registry could strengthen precision.

Conclusions

We found that patients who had undergone an OLT and developed AKI had a greater DPP deficit and CVP increase compared with patients without AKI. These results indicate that these deficits might be considered as an adjustable hemodynamic target to prevent AKI. Because of the high incidence of AKI in this population and its clinical impact, an adequate perioperative management of renal function should be the focus for preventing AKI.

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