Duration of Vecuronium-Induced Neuromuscular Block as a Predictor of Liver Allograft Dysfunction

GENERAL ARTICLES

Duration of Vecuronium-Induced Neuromuscular Block as a Predictor of Liver Allograft Dysfunction Cara L. Lukin, MD, H. A. Tillmann Hein, MD, Thomas H. Swygert, MD,

Thomas C. Gunning III, MD, Timothy R. Valek, MD, Steven K. Donica, MD,

Ross B. Nelson III, MD, and Michael A. E. Ramsay, MD

Departments of Anesthesiology and Pain Management, Baylor University Medical Center, and University of Texas Southwestern Medical Center, Dallas, Texas

The major causes of liver graft failure are acute rejection, technical failure, and primary nonfunction (PNF). This study was undertaken to determine whether delayed return of neuromuscular function correlates with allograft primary dysfunction in humans given vecuronium. Twenty-two adult patients undergoing orthotopic liver transplantation were given an initial dose of vecuronium, 0.1 mg/kg intravenously (IV). All patients recovered from vecuronium-induced neuromuscular block prior to explantation. No additional neuromuscular blocker was given until the liver graft was implanted and reperfused. Fifteen minutes after reperfusion an- other 0.1 mg/kg vecuronium was given IV and recovery time from attaining complete neuromuscular block to return of the fourth twitch of a train-of-four was recorded. Patients were divided into three groups according to postoperative liver function. Group I consisted of 17 patients with immediate normal liver graft function. Group II consisted of four patients with primary dysfunction (PDF) [peak aspartate aminotransferase CAST)

and alanine aminotransferase (ALT) >2000 U/L, prothrombin time >16 s, and poor quality and quantity of bile within 3 days postoperatively] which eventually recovered normal function. Group III consisted of one patient with PNF (uncorrectable coagulopathy, severe metabolic acidosis, rising AST and ALT, and minimal or no bile output), whose graft never recovered. Recov- ery time in Groups II and III was prolonged compared to Group I (P < 0.05). Recovery time in Group III was prolonged compared to Group II (P < 0.05). A test based on these results using a recovery time of >135 min as a predictor of PDF has a sensitivity and specificity of 80% and 76%, respectively. The positive and negative predictive values are 50% and 93%. Duration of neuromuscular block after vecuronium administration appears to be an early predictor of liver allograft function.

(Anesth Analg 1995;80:526-33)

A llograft failure remains a significant cause of morbidity and mortality and has led to retransplantation in lo%-20% of all liver trans-

plants performed (1). The major causes of graft failure are acute rejection, technical failure, and primary nonfunction (PNF); PNF occurs in 2%-23% of transplants and is the most severe form of the spectrum of posttransplant primary dysfunction (PDF) (2). PNF is irreversible and retransplantation is the only treatment. Prostaglandin E, @‘GE,) is efficacious in reversing the course of lesser degrees of PDF (3). The most rapid possible diagnosis of PDF will enable early interven- tion with PGE, and possible graft salvage.

Accepted for publication October 4, 1994. Address correspondence and reprint requests to Michael A. E.

Ramsay, MD, Department of Anesthesiology and Pain Manage- ment, Baylor University Medical Center, 3500 Gaston Avenue, Dal- las, TX 75246.

526 An&h Analg 1995;80:526-33

Investigators have evaluated many different markers for PDF, but none is ideal. Some are nonspecific for liver function and others are cumbersome, expensive, or slow in turn-around time (4). Moreover, none of these tests can definitively distinguish a graft with irreversible dysfunction (PNF) from one that has reversible initial poor function.

Vecuronium, a monoquaternary steroidal neuromuscular blocking drug, is sequestered in, and metabolized predominantly by, the liver (5). The return of neuromuscular function is monitored with the use of a peripheral nerve stimulator which is efficient, quick, and inexpensive. Prolonged vecuronium block thus may be an early indicator of PDF. Pittet et al. (6) have demonstrated -in pigs that prolonged vecuronium neuromuscular block may be an early indicator of graft dysfunction. This study was undertaken to determine whether delayed return of neuromuscular function after vecuronium-induced neuromuscular

01995 by the International Anesthesia Research Society 0003-2999/95/$5.00

ANESTH ANALG 1995;80:526-33

LUKIN ET AL. 527 VECURONIUM PREDICTOR OF LIVER FUNCTION

block in the early neohepatic period correlates with allograft PDF in humans.

Methods After obtaining institutional approval and informed consent, 22 patients underwent orthotopic liver transplantation. Two patients were undergoing retransplantation; the first patient because of hepatic artery thrombosis, and the second because of cholestatic failure of the initial graft.

Anesthesia was induced in a rapid sequence man- ner with thiopental (3-4 mg/kg intravenously [IV] and either fentanyl (3-4 pg/kg IV) or sufentanil(O.2- 0.3 pg/kg IV>. Skeletal muscle relaxation for endotra- cheal intubation was accomplished by administration of succinylcholine (1.3-1.5 mg/kg IV). Positive pressure ventilation was initiated with 50% oxygen in air, tidal volume lo-12 mL/kg, and respiratory rate of 6-12 breaths/min. Anesthesia was maintained with isoflurane (0.3-0.8 end-tidal vol %) and supplements of either fentanyl or sufentanil titrated to maintain hemodynamic stability.

The depth of neuromuscular block was monitored by stimulating the facial nerve with a MiniStim MS-II peripheral nerve stimulator (Life-Tech, Inc., Houston, TX) via cutaneous electrodes. The facial nerve was chosen as it was easily accessible, whereas access to the ulnar nerve was impeded by other patient care instrumentation. The train-of-four mode was applied, wherein supramaximal stimuli were delivered at a frequency of 2 Hz for 2 s to yield one group of four stimulus pulses. The number of resulting contractions of the orbicularis oculi muscle was visually counted by two observers.

After ascertaining the return of four baseline twitches after succinylcholine administration, vecuronium (0.1 mg/kg) was given IV. This dose was chosen because it is already part of the clinical routine and one of the aims of the study was to stay as closely as possible within the bounds of clinical practice. This initial administration of vecuronium occurred before commencement of the surgical procedure. The train- of-four was monitored to assure that all patients had the ability to recover from vecuronium-induced neuromuscular block prior to explantation of their diseased liver. In a subset of patients, when there were O/4 twitches on the train-of-four, the time was recorded. The response to the train-of-four was then monitored every 5 min until three twitches recovered; thereafter, it was observed every 2 min until four of four twitches were attained. The time of recovery of four twitches was recorded (in minutes), and therefore, the time of baseline return of neuromuscular function was known. After the return of four twitches no additional neuromuscular blocker was given until

the donor liver was implanted and reperfused. It was again confirmed that all four twitches on the train-of- four returned to baseline before administration of the second, neohepatic dose of vecuronium, which occurred 15 min after reperfusion. The depth of neuromuscular block was again monitored as described above, and the time (in minutes) for return of four twitches after the neohepatic dose of vecuronium was recorded. All donor livers were preserved in Univer- sity of Wisconsin solution and veno-venous bypass was used in all procedures.

Body temperature was monitored via the temperature thermistor of an indwelling pulmonary artery catheter and was maintained with the use of a warming blanket, forced-air warming device, warmed IV fluids, and warmed inspiratory gases. End-tidal isoflurane concentration was monitored with continuous mass spectrometry. The average end-tidal concentration during the operation was recorded.

Except for one patient, all received amphotericin B and either imipenem or vancomycin and ciprofloxacin preoperatively. One patient received gentamicin, met- ronidazole, and ceftazidime in addition to amphotericin and vancomycin preoperatively.

The effect of temperature on return of neuromuscular function was evaluated using measurements doc- umented on the continuous temperature record. Im- mediately upon arrival to the intensive care unit, and at regular intervals thereafter, serum creatinine and serum aspartate aminotransferase (AST), and serum alanine aminotransferase (ALT) were measured. For the purpose of this study, initial serum creatinine values and peak serum transaminases were recorded. Peak transaminases were the highest AST and ALT values within three postoperative days.

The postoperative course was observed closely, and the patients were divided into three groups according to outcome. Group I consisted of patients who had immediate normal liver graft function as defined by peak postoperative AST and ALT ~2000 U/L, normal quality and quantity of bile production, and lack of coagulopathy. Groups II and III represented all patients with abnormal postoperative liver function. Group II consisted of patients with initially poor functioning grafts, defined as AST and ALT >2000 U/L and prothrombin time >16 see within the first 3 days posttransplant (7). Group III consisted of patients with primary nonfunctioning grafts; PNF was defined as non-life-sustaining liver graft function, manifested by uncorrectable coagulopathy, metabolic acidosis, rising AST and ALT, and minimal or no bile output.

For statistical analysis, Student’s t-test and the Wil- coxon rank sum test were used for comparisons between groups. The Wilcoxon test was applied when there was a small sample size in one group. Spear- man’s correlation was used to evaluate the association

528 LUKIN ET AL. ANESTH ANALG VECURONIUM PREDICTOR OF LIVER FUNCTION 1995;80:526-33

Table 1. Etiology of Liver Failure in Patients Undergoing Orthotopic Liver Transplantation (n = 22)

Number Percent

Chronic active hepatitis (C) 9 41 Cryptogenic cirrhosis 4 18 Primary biliary cirrhosis 3 14 Sclerosing cholangitis 2 9 Failure of initial graft 2 9 Laennec’s cirrhosis 1 4.5 Autoimmune hepatitis 1 4.5

between duration of neuromuscular block and peak AST and ALT. It was also used to determine the impact of weight, temperature, renal function, end- tidal isoflurane concentration, and exposure time to isoflurane on the duration of the neuromuscular block. Exposure time to isoflurane was calculated by divid- ing the average end-tidal isoflurane concentration by 1.15, the minimal alveolar anesthetic concentration, and then multiplying by the time from induction to the neohepatic return of the train-of-four. A P value <Cl.05 was considered statistically significant. An analysis of sensitivity and specificity of recovery time as an indicator of allograft function was performed.

Results

Twenty-two patients, 9 women and 13 men, aged 21-68 yr, none suffering from neuromuscular disor- ders, were included in this study. The etiologies of their end-stage liver disease are displayed in Table 1.

All 22 patients had experienced the return of the train-of-four prior to veno-venous bypass and explantation of the liver. In 17 patients the time of the return of the train-of-four was recorded. The paleohepatic phase recovery time of the train-of-four in patients who later proved to have received a normally functioning liver transplant was not significantly different from that in patients who later had primary graft dysfunction (Table 2).

Recovery time from neuromuscular block was recorded in 22 patients in the neohepatic phase. Of these, 17 had normal postoperative liver function and five did not. Of the five with PDF, four patients met the criteria for Group II (initial poor function) and one met the criteria for Group III (PNF). All patients in Group II eventually developed adequate liver function, two of them after having received PGE,. The patient in Group III required explantation of the first graft within 24 h. Retransplantation was performed within 36 h with a non-cross-matched liver; this second organ functioned well for 2 days but then underwent severe acute rejection. A third liver was implanted; this organ functioned well, but the patient eventually died of sepsis.

The 17 patients in Group I with normal postoperative liver function had a significantly shorter recovery time on the train-of-four (113.5 + 8.7 min) as compared to the five patients with PDF in Groups II and III (165.4 t 26.9 min, P < 0.05). A comparison between patients with normal postoperative liver function (Group I) and those without (Groups II and III) is shown in Table 2.

In most patients recovery from vecuronium- induced block required more time in the neohepatic phase than prior to explantation of the diseased liver. The mean time difference was not significantly different in regard to graft function classification. Two patients in Group I had shorter recovery times in the neohepatic phase than prior to explantation. Both of these patients were in fulminant hepatic failure.

A comparison between the patient with PNF and all others is shown in Table 3. This patient had a significantly prolonged recovery time as compared to all others (267 min for Group III, 117.2 ? 7.9 min for Groups I and II; P < 0.05). When the second, initially functioning graft was implanted into this same patient, the time for return of four twitches was shorter, being 125 min.

A strong correlation was found between peak AST and ALT and time of return of four twitches, as shown in Tables 2 and 3. The Spearman correlation coefficient was 0.62 (P < 0.05) for AST; for ALT it was 0.70 (P < 0.05). There was a negative correlation between the average end-tidal concentration of isoflurane and recovery time of the train-of-four, the Spearman correlation coefficient being -0.49 (P < 0.05). In the group comparison, however, no difference between Groups I and II/III in regard to isoflurane concentration could be detected (Table 4).

There was no correlation between the return of the train-of-four in the neohepatic period and weight, serum creatinin, body temperature, exposure time to isoflurane, or age (Tables 4 and 5).

To assess sensitivity and specificity of a test to predict liver graft function based on these results, we grouped patients in the order of increasing neohepatic train-of-four time (Table 6).

Using a neohepatic train-of-four time of ~135 min as an indicator of graft dysfunction, this test has a sensitivity of 80% and a specificity of 76%. The positive predictive value is 50%, and the negative predictive value is 93% (Table 7).

Discussion

Our results suggest that recovery from vecuronium- induced neuromuscular block required more time after reperfusion of a liver allograft than prior to the

ANESTH ANALG LUKIN ET AL. 529 1995;80:526-33 VECURONIUM PREDICTOR OF LIVER FUNCTION

Table 2. Comparison Between Patients with Normal Immediate Postoperative Allograft Function and Those with Primary Dysfunction

Normal function Primary dysfunction P value

Paleohepatic recovery time of TOF (min) 74.9 + 7.5 (n = 15) 60.0 t 19.9(n = 2) NS Neohepatic recovery time of TOF (min) 113.5 + 9.0 (n = 17) 165.4 ” 27.3 (n = 5) co.05 Difference between paleo- and neohepatic TOF times (mm) 37.0 c 11.9 (n = 15) 128.5 + 93.5 (n = 2) NS Peak aspartate aminotransferase (U/L) 835.5 2 130.3(n = 17) 5892.8 k 2161.3 (n = 5) CO.05 Peak alanine aminotransferase (U/L) 737.8 + 129.1(n = 17) 3648.2 + 477.2(n = 5) co.05 Peak prothrombin time (s) 17.7 t 0.5 (n = 17) 19.4 + 1.6 (n = 5) co.05

All data expressed as mean t sli. NS = not significant; TOF = train-of-four.

Table 3. Comparison Between Patients with Primary Nonfunction and all Others

Recovery time TOF (mm) Peak aspartate aminotransferase (U/L) Peak alanine aminotransferase (U/L) Peak prothrombin time (s)

All data expressed as mean -C SE. TOF = train-of-four. *Normal and initially poor graft function.

All others”

117.2 + 7.9 1426.2 + 274.5 1254.3 t 276.5

21.2 2 0.4

Primary nonfunction

267.0 14488.0 4442.0

25.2

P value

co.05 co.05 co.05 co.05

Table 4. Comparison Between Variables Affecting Vecuronium Metabolism in Patients with Normal Immediate Allograft Function Versus Primary Dysfunction

Variable P value

Serum creatinine (mg/dL) Average temperature (“C) Average end-tidal isoflurane concentration (vol %) Exposure time to isoflurane (MAC hours) Age (yr) Weight (kg)

All data presented as mean 2 SB. NS = not significant; MAC = minimum alveolar anesthetic concentration.

Normal

1.01

Primary function

+- 0.14

dysfunction

1.00 t 0.10 NS 34.27 + 0.24 34.61 + 0.32 NS 0.524 2 0.035 0.428 + 0.085 NS 2.737 2 0.126 2.992 + 0.364 NS

50.1 If: 0.5 55.6 + 4.9 NS 69.69 ? 3.86 71.52 + 7.83 NS

Table 5. Comparison Between Variables Affecting Vecuronium Metabolism in Patients with Primary Nonfunction Versus all Others

Variable All others Primary

nonfunction P value

Serum creatinine (mg/dL) 1.01 2 0.12 0.90 NS Average temperature (“C) 34.29 2 0.20 35.50 NS Average end-tidal isoflurane concentration (vol %) 0.518 + 0.031 0.175 NS Exposure time to isoflurane (MAC hours) 2.75 rt 0.75 1.28 NS Age (yr) 51.9 + 2.6 38.0 NS Weight (kg) 69.4 + 17.0 85.6 NS

All data expressed as mean IT SB. NS = not significant; MAC = minimum alveolar anesthetic concentration.

explantation of the native liver. This probably indi- cates temporary functional impairment of the transplanted organ. In some patients, as in two of our series, the functional status of the allograft may be better than that of the failing native liver. In those patients recovery time from vecuronium was shorter.

Patients who later met established criteria for PDF

of the allograft proved to have significantly longer recovery times than patients with normal graft function. This difference can be used as a test to predict graft function. This test has a positive predictive value of 50% and a negative predictive value of 93%. There- fore, obtaining a positive test would result in 50% correctly identified cases of PDF; the other 50% would

530 LUKIN ET AL. ANESTH ANALG VECURONIUM PREDICTOR OF LIVER FUNCTION 1995;80:526-33

Table 6. Rank Order of Patients According to Neohepatic Recovery Time from Vecuronium Block

Patient No.

Train-of-four time (min) Graft function

14 11 21 15 18 5 9 8 2 7

13 20

4 22 16 19 12

6 3 1

10 17

36 Normal 45 Normal 75 Normal 95 Normal

100 Normal 100 Normal 110 Normal 110 Primary dysfunction 115 Normal 120 Normal 125 Normal 125 Normal 130 Normal 135 Normal 140 Primary dysfunction 145 Primary dysfunction 148 Normal 150 Normal 160 Normal 160 Normal 165 Primary dysfunction 267 Primary dysfunction

actually have adequate liver function. Therapeutic interventions based on this test, such as prostaglandin treatment, may therefore be applied to twice as many patients as need it. On the other hand, if, based on this test, interventions are initially withheld then that de- cision would be correct in 93% of cases. In light of the high price of prostaglandin our test may help contain costs.

Despite the major advances in liver transplantation over the last decade, PNF remains one of the main causes of graft failure. It represents up to 23% of the etiology of graft failure; the balance of the causes of graft failure are acute rejection (57%) and technical failure (20%) (8).

Marked improvements in immunosuppression have improved graft survival. The use of intraoperative electromagnetic flow monitoring and early postoperative ultrasound evaluation of hepatic blood flow have enhanced outcome in the case of unsuspected technical shortcoming (9). Nevertheless, PNF persists as an important barrier to graft and patient survival.

In 1989 Greig et al. (3) reported that 9 of 10 patients suffering from PDF were alive and well 3-23 mo post- transplantation after treatment with PGE,. No comparison was made in that study between the timing of diagnosis of PDF and response. Moreover, at that time, there was no uniform definition of PNF nor its relationship to PDF. PNF is now known to be the most severe form of PDF and is irreversible. It is advanta- geous to differentiate a true PNF as early as possible since these patients require retransplantation. A delay

in retransplantation can lead to the development of multi-organ-system failure, and it has been shown that multi-organ-system failure decreases the chance for survival in retransplanted patients (10).

For these reasons, many markers for an early diagnosis of PDF have been evaluated. Bile production has long been considered an important predictor (1). Re- covery of clotting function, peak rise in AST and ALT, and peak rise in bilirubin have been studied, but are not specific (2,8). Several other indicators have been considered, including increase in oxygen consumption (4,111, degree of hyperglycemia (121, increase in end- tidal CO2 (13), synthesis rate of hepatic proteins (14), the clearance rate of amino acids (151, the activity of 1ecithin:cholesterol acyltransferase (16), and the metabolism of lidocaine to monoethylglycinexylidide (MEGX) (17). While some of these tests may be reliable indicators of graft function, they are all suboptimal. Those in the former group are nonspecific for liver function and those in the latter are cumbersome, expensive, and slow in turn-around time. The difficulty of diagnosis is epitomized by the need to develop a summation score of seven variables which include total oxygen consumption, liver enzymes, and ketone body ratio, modified with a dimension factor and then a weighting factor to produce a score which differen- tiates between reversible and irreversible dysfunction (18). Even so, the score cannot be assessed until 36-48 h after reperfusion. Yet, no other test has been available to differentiate reversible from irreversible graft function.

Recently, a comparison of sensitivity, specificity, and positive and negative predictive values of liver function prediction tests was reported. The MEGX test has a sensitivity of 95% and a specificity of 73%. The positive and negative predictive values were 55% and 98%, respectively (19). Other tests, based on synthetic functions of the graft, were less sensitive. The test proposed in this paper has a sensitivity, specificity, and positive and negative predictive values com- parable to the MEGX test. In contradistinction to the MEGX test, measuring recovery time from vecuronium-induced neuromuscular block does not require injection of any otherwise not indicated medication, does not generate any cost, and the result is available frequently before the patient leaves the operating room.

The train-of-four stimulus is a reliable monitor of neuromuscular block and thus, indirectly, of the amount of drug present in plasma. Ali et al. (20,21) originally described the use of trains-of-four stimuli in assessing competitive block and showed that the ratio of the fourth twitch to the first quantifies the degree of block. Waud and Waud (22) then demonstrated that the fourth twitch reappears when 25%30% of receptors have become free of drug. Lee (23) confirmed this


Table 7. Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value of the Vecuronium Recovery Test for Liver Graft Function

Definition Calculation

Sensitivity True positive true positive + false negative

Specificity

Positive predictive value

Negative predictive value

True negative false positive + true negative

True positive true positve + false positive

True negative false negative + true negative

finding and showed that the visual reappearance of the fourth twitch (determined by visually counting the number of responses to train-of-four stimulation) ac- curately corresponds to this degree of block. He showed that the train-of-four count method is as ac- curate as measuring fade and virtually free from in- strumental errors.

In this study, the train-of-four count was used as described above. The return of the fourth twitch was used to represent the state when 25%-30% of receptors were free of drug. Vecuronium effect, as measured by twitch, is closely related to plasma drug concentration (24). Hepatic sequestration and clearance are the main routes of disappearance of vecuronium from plasma, thus linking hepatic function to return of the fourth twitch.

Vecuronium bromide is a monoquaternary neuromuscular blocking drug originally derived from pancuronium (25). Because its disposition is determined mainly by the liver and its pharmacokinetics have been shown by most investigators to be unchanged in patients with renal disease, it is a suitable drug with which to monitor liver function (5,26). Bencini et al. (5) have shown that greater than 50% of an IV dose of vecuronium is present in the human liver 30 min after injection and that both unchanged drug and its me- tabolites are excreted in bile. In a rat model they found that 70% of a dose of vecuronium administered into the portal circulation was excreted in the bile within 2 h and 22% remained in the liver; of the drug excreted in bile almost 50% was present as the 3-hydroxy metabolite (27). Lynam et al. (281, on the other hand, found with isoflurane anesthesia a prolongation of vecuronium effect in patients without renal function when compared to patients with normal renal function. The clinical duration of the vecuronium effect varies quite widely among patients. It is possible that this variation in duration is responsible for the false- positive test results, thereby lowering the specificity of the test.

Intraoperatively assessing the return of neuromuscular function after vecuronium block by monitoring the train-of-four appears to be a good method of pre- dicting primary graft dysfunction. Our data demon- strate a statistically significant prolongation of recovery time in patients with PDF. This diagnosis enables early commencement of treatment with PGE,.

As vecuronium appears to be sequestered in the liver before it is metabolized, it follows that either impaired hepatic uptake or impaired hepatic metabolism (or both) may be responsible for the defect in drug clearance in PDF grafts (29).

Our data are controlled for renal function. There was no significant association between renal function as measured by serum creatinine and time of return of the fourth twitch. Obesity may prolong vecuronium effect (30). We saw no correlation between weight and recovery time from vecuronium in our patients. There was also no impact by temperature or age on recovery of the train-of-four. There was an association between end-tidal isoflurane concentration and time of fourth twitch return. However, the relationship is opposite to the one expected if isoflurane concentration had con- tributed to duration of block; as volatile anesthetics are known to enhance neuromuscular block, a higher isoflurane concentration should have led to a longer time of block. An opposite effect was seen in this study, leading to the deduction that longer block times were probably not caused by isoflurane enhancement. It may, however, be possible that patients with better functioning liver grafts needed higher concentrations of volatile anesthetic, because their new livers dis- posed of the narcotics more rapidly. There also was no correlation with the duration of isoflurane exposure. Antibiotics may influence the duration of vecuronium effect (31). All patients received amphotericin B which is not known to have an effect on block. Antibiotics used in our study patients that are known to prolong

532 LUKIN ET AL. VECURONIUM PREDICTOR OF LIVER FUNCTION

ANESTH ANALG 1995;80:526-33

neuromuscular block include gentamicin and metron- idazol. Only one patient received these drugs, and he demonstrated a relatively short recovery time (100 min).

There has been a recent report of prolonged vecuronium paralysis due to the active 3-desacetyl metabolite after long-term administration of the drug (32), however, this mechanism does not appear to be responsible for the prolonged neuromuscular block in the PDF patients in our study. The patients in that report received large total doses of vecuronium over a prolonged period of time (337 mg over 6 days for the first patient and 83 mg over 2 days for the second). They both had severely impaired renal function (creatinine clearance of 5.0 mL/min for the first patient and 3.6 mL/min for the second). The prolonged paralysis was thought to be due to the active 3-desacetyl metabolite, which is not only excreted in the urine, but also sequestered in a theoretic storage compartment which then equilibrates slowly with the central compartment (plasma). Increased vecuronium require- ment during periods of heavy blood loss has also recently been reported (33). In our study one patient with PDF received 10 units of packed red blood cells during the postreperfusion stage. It may well be that the prolonged recovery time in this patient was fore- shortened. In the other patients red cell replacement as an indicator of blood loss was small, apparently unrelated to graft function or recovery time from vecuronium-induced block. In our study, no patient with prolonged block had severe renal impairment and no patient received large enough doses of vecuronium over a long enough period of time to be likely to develop sequestration of 3-desacetylvecuronium into a separate storage compartment. Finally, the patient with PNF who received a second graft allowed a direct comparison to be made between the presence and absence of renal failure and its impact on duration of neuromuscular block. Despite receiving a higher cumulative dose of drug and having worse renal function during the second transplant (serum creatinine was 2.6 mg/dL vs 0.9 mg/dL after the first transplant), it took a markedly shorter time to recover neuromuscular function (125 min vs 267 min during the first transplant).

Fortunately, only one of our patients met the criteria for PNF. We realize that a group of one weakens the statistical analysis. However, the clinical importance of a diagnosis of PNF, and the fact that the recovery time in this patient was so much longer than in the other patients with PDF, prompted us to speculate that this test may enable an early diagnosis of irreversible PNF. We believe this merits further study. An earlier diagnosis of PNF may reduce delay in retransplantation, which is known to lead to the development

of multi-organ-system failure, decreasing the chance of survival in retransplanted patients. It is also of interest that when this patient underwent retransplantation with the second liver, a comparison was allowed wherein other variables affecting vecuronium metabolism and neuromuscular block were isolated, and the effect of liver function on duration of block was evaluated. The recovery time with the second liver graft was 125 min, as opposed to 267 min with the first liver graft. Other variables remained constant, except for the renal function: the serum creatinine had increased to 2.6 mg/dL during the second transplant from 0.9 mg/dL at the time of the first transplant. This decrease in renal function would have tended to prolong the recovery time if it had been an important variable. As the recovery time was impressively shorter in the same patient after the second liver transplant, it appears that renal function did not have an important role in the duration of the block and that the effect of liver function alone on block duration was observed. This second liver graft functioned well for 2 days, although it underwent severe, acute rejection (biopsy proven) after that time.

In conclusion, the duration of neuromuscular block after vecuronium administration in the neohepatic phase appears to be a good predictor of graft dysfunction. This test is expedient, efficient, and inexpensive. In addition, further experience may confirm that this method distinguishes irreversible PNF from reversible initial poor function.

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Duration of Vecuronium-Induced Neuromuscular Block as a Predictor of Liver Allograft Dysfunction

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