Noninvasive Monitoring of Cerebral Perfusion by Transcranial Doppler During Fulminant Hepatic Failure and Liver Transplantation

Abstract

Survival in patients with fulminant hepatic failure (FHF) treated medically, rather than surgically, ranges from 12%-67% (mean 39%), depending on the cause of the disease [1]. The major cause of mortality is increased intracranial pressure (ICP) from brain edema [2]. For patients with a poor prognosis [3], orthotopic liver transplantation may be the definitive treatment [4], even though, only a few years ago, some considered this treatment ineffective by the time patients reached Grade 4 encephalopathy [5]. ICP monitoring allows physicians to use specific therapy to control intracranial hypertension. Continuous measurement of ICP perioperatively in the management of FHF has been associated with a survival rate of 54%-74% in a series of six to 23 patients [6-9], which is generally higher than with medical means [1], and was as high as 92% for the selected group who had undergone liver transplantation [6]. Such invasive monitoring, however, is especially risky in FHF patients with coagulopathy, in whom the incidence of bleeding from ICP monitoring ranges from 5%-22% [6,8] with a mortality rate of 60% [6]. Although the use of ICP monitoring for FHF has become more routine [8], not all centers support the use of this invasive monitoring. We describe a patient with FHF and brain edema who underwent liver transplantation and whose cerebral perfusion was monitored noninvasively by transcranial Doppler (TCD) imaging, as well as invasively by ICP. The noninvasive technique provided adequate information when cerebral perfusion was low, comparable with the invasive technique, and allowed intracranial hypertension to be diagnosed and treated effectively. Case Report A 50-yr-old woman with a 1-mo history of acute hepatitis with negative serologies presented with jaundice only, without ascites or bleeding; however, she became encephalopathic within a week. She was transferred to our tertiary care center for medical management and possible liver transplantation. Within five days, the neurologic status deteriorated from being comatose and reacting to painful stimuli on admission (Stage 2-3) to deep coma without response (Stage 4). Five days postadmission, the trachea was intubated, and the patient was hyperventilated and scheduled for surgery within a week postadmission. Preoperatively, prothrombin time was 25 s and partial thromboplastin time 52 s, which was treated with fresh-frozen plasma. Bilirubin was 39.1 mg% (15.2 mg% direct). Electrolyte and glucose concentrations, blood urea nitrogen, creatinine, and protein were normal. Electrocardiogram showed normal sinus rhythm (79 bpm, low-voltage), echocardiogram showed normal left ventricular function, and ejection fraction was >50%. Chest radiogram was normal. Computed tomography scan of the brain showed normal ventricles and no edema, mass effect, or shift. Electroencephalogram did not reveal focal or lateralizing alterations; TCD imaging revealed normal flow velocity (FV; Figure 1A). The patient had no signs of renal impairment during hospitalization.Figure 1: Transcranial Doppler (TCD) images of cerebral flow velocity from a patient during different stages of liver transplantation and treatment (see Figure 3 and Figure 4 for events). The "cursor" value is diastolic flow velocity (cm/s). This value was determined manually, as well as by the monitor (black shading). A. Baseline: Preoperative flow velocity in the right middle cerebral artery (RMCA) is normal; pulsatility difference is 48 cm/s. B. Before anesthetic induction: Flow velocity is recorded from the RMCA before hemodynamic support and intracranial decompression; pulsatility difference is 60 cm/s (Event 1). During surgery, calculation was made manually and not according to automatic reading of the TCD recording (peak systolic flow velocity is 78 cm/s). C. During revascularization of the transplanted liver: Flow velocity is recorded from RMCA; at this point, the TCD recording mistook systolic "dicrotic notch" for maximal peak, which is actually 75 cm/s; pulsatility difference is 62 cm/s (Event 15). "Depth" refers to the depth to which the probe penetrates. PI, pulsatility index.Because deep coma suppressed neurologic signs, ICP monitoring was initiated. After treatment for coagulopathy (partial thromboplastin time, 40 s) with fresh-frozen plasma, a subdural catheter was inserted and connected to a closed, sterile monitoring system (Model ER, Camino Laboratories, San Diego, CA) for continuous ICP monitoring. This system does not measure pressure directly, but uses fiberoptic technology. Initially, ICP was 10-20 mm Hg; to keep it <15 mm Hg, hyperventilation, optimal head positioning, intravenous (IV) mannitol, and steroids were administered. Treatment was maintained for three days with good response. However, when the patient arrived at the operating room, ICP was 35-40 mm Hg, and cerebral perfusion pressure (CPP; mean blood pressure--ICP) was 45 mm Hg. TCD imaging demonstrated low diastolic flow (Figure 1B; Figure 2; and Figure 3, Event 1). To keep CPP >50 mm Hg, we administered treatment to increase systemic pressure and decrease ICP simultaneously. To increase systemic pressure, the following cardiotonic drugs were administered: dopamine, 5 to 10 micro gram centered dot kg centered dot min-1; epinephrine, bolus and infusion, 0.01 micro gram centered dot kg centered dot min-1; phenylephrine; and calcium chloride when ionized calcium decreased to <2.0 mEq/L. Sodium thiopental, mannitol, and furosemide were given to decrease ICP. Once CPP was >50 mm Hg and diastolic FV increased (Events 2-4 in Figure 2 and Figure 3), we put the patient in the Trendelenburg position temporarily to place central venous and pulmonary artery catheters. Care was taken to place the catheters apart from one another and to use the external jugular, subclavian, and basilic veins, rather than both internal jugular veins, which would increase impedance to venous return from the brain bilaterally.Figure 2: Changes in cerebral perfusion pressure (CPP) and diastolic component of transcranial Doppler flow velocity recording (TCD-D) in a patient during liver transplantation (Events 1-29; periods between events may vary in time). Event 1, before treatment and anesthetic induction; Event 2, after treatment and before anesthetic induction, Event 4, after anesthetic induction and before incision; Event 12, end of Stage 2 of liver transplantation, clamping; Event 15, early Stage 3 (revascularization, unclamping); Event 24, late Stage 3 (manipulations); Event 28, end of surgery before transport of the patient to the intensive care unit.Figure 3: Changes in intracranial pressure (ICP) and diastolic component of transcranial Doppler recording (TCD-D) in a patient during liver transplantation surgery (Events 1-29; periods between events may vary in time; see events in Figure 2).Anesthesia was induced and maintained with fentanyl and isoflurane (0.2%-0.5% range) in 50%-100% O2/air, and IV pancuronium was used for muscle relaxation. In addition to the basic monitoring, the following were monitored continuously: invasive systemic and central pressures, mixed venous O2 saturation, ICP, and TCD. To establish a neurophysiologic status immediately preoperatively, evoked potentials were obtained before any anesthetic or surgical manipulation in the operating room and were normal. After cannulation during anesthesia, TCD images and ICP were within normal limits (Figure 2 and Figure 3, Event 4). The goal during the operation was to maintain CPP >50 mm Hg. Epinephrine and calcium chloride were required throughout the procedure to maintain effective systemic pressure (central venous pressure and wedge pressure at 10-15 mm Hg with fluid administration to maintain filling pressure). Administration of diuretics, furosemide, and mannitol maintained high urine formation and decreased ICP. During Stage 1 surgery (dissection and manipulation of the liver and its vessels), which reduces venous return, crystalloids (saline 0.9% and plasmalyte A) were administered and titrated to central filling pressure and CPP. Also, packed red blood cells, fresh-frozen plasma, and platelets were administered. During Stage 2 (the anhepatic stage that lasted 2.5 h), with the liver vessels clamped, central venous pressure was 5 mm Hg, CPP <25 mm Hg and the diastolic component of the TCD (TCD-D) <5 cm/s (Figure 2, Event 12). All reversed within minutes by volume loading, establishing (as planned) veno-veno bypass, and epinephrine administration,without any use of pharmacologic agent to reduce ICP (i.e., barbiturates). During unclamping and liver reperfusion, CPP was again reduced temporarily (<50 mm Hg), and TCD imaging showed low (<15 cm/s) diastolic FV and high pulsatility difference (PD, 62 cm/s; Figure 1C and Figure 2, Event 15). Intravascular fluid replacement, calcium chloride, and epinephrine were effective. Later, in Stage 3 (neohepatic stage), CPP was within advisable limits (>60 mm Hg), and cerebral FV monitoring was normal (Figure 2 and Figure 3, Events 24-28); all ICP/CPP problems during Stages 2 and 3 were related and treated as systemic pressure/perfusion problems. ICP slowly decreased to 19 mm Hg by the end of surgery, and diuresis was 3500 mL during the 12-h operation. The hemodynamic stability enabled the dose of epinephrine to be decreased to 0.01 micro gram centered dot kg centered dot min-1. A total of 22 L of crystalloid and 16 U of packed red blood cells, 16 U of fresh-frozen plasma, and 10 U of platelets were administered for the entire procedure. The overall relationship between TCD PD and diastolic CPP (diastolic blood pressure--ICP) during anesthesia and surgery is described in Figure 4. There was an inverse relationship with good correlation (r = 0.82, n = 29) for nonlinear regression. Also, TCD FV indices (i.e., PD and pulsatility index [PI]) had a lower nonlinear correlation with mean CPP (mean blood pressure--ICP; Table 1, but that nonlinear correlation was always exponential, second-order polynomial regression type, with a change in relationship <50 mm Hg mean CPP Figure 5, A and B. Evaluation of other intraoperative FV parameters and indices (including PI or mean FV in our study) did not demonstrate as good a relationship with CPP or ICP as did PD Table 1. Only the relationship of PI with diastolic CPP or mean CPP had an r2 value similar or better when compared with the same relationship of PD with cerebral pressures (0.66 vs 0.68 and 0.59 vs 0.47 [exponential nonlinear relationship]), but the PI-CPP relationship had a lower r value for linear relationship when compared with the PD-CPP relationship Table 1. After the operation, the patient was taken to the intensive care unit, where she began to respond appropriately after 48 h. On the third postoperative day, ICP monitoring was discontinued, and on the sixth day her trachea was extubated. She continued to do well with no apparent neurologic deficit and was discharged from the hospital 7 wk after the operation without any additional complications.Figure 4: Correlation of diastolic blood pressure--intracranial pressure (ICP) (diastolic cerebral perfusion pressure [= "diastolic" CPP]), with transcranial Doppler systolic--diastolic flow velocity (pulsatility difference) in a patient during liver transplantation. For nonlinear (exponential polynomial) regression (y = a + bex p[-x/c]): full line; r = 0.82; n = 29 data points; FitstdErr = 5.46; Fstat = 27.52; a = 26.03; b = 56.01; c = 38.79. For linear regression (y = a + bx): dotted line; r = 0.80; n = 29 data points; FitstdErr - 5.66; Fstat = 48.45; a = 71.61; b = -0.61.Table 1: Linear and Nonlinear Correlation (r2 Values) Between Cerebral Perfusion Pressure (Diastolic and Mean) and Intracranial Pressure Values and Flow Velocity (Values and Indices) in a Patient During Orthotopic Liver TransplantationFigure 5: A. Correlation of mean blood pressure--intracranial pressure (ICP) (= mean cerebral perfusion pressure [CPP]), with transcranial Doppler systolic-diastolic flow velocity (pulsatility difference) in a patient during liver transplantation. For nonlinear (exponential polynomial) regression (y = a + bex P[-x/c]): r = 0.68; n = 29 data points; FitstdErr = 7.00; Fstat = 11.71; a = 37.73; b = 99.32; c = 23.77. B. Correlation of mean blood pressure--ICP (= mean CPP), with transcranial Doppler pulsatility index in a patient during liver transplantation. For nonlinear (exponential polynomial) regression (y = a + bex P[-x/c]): r = 0.77; n = 29 data points; FitstdErr = 0.29; Fstat = 18.99; a = 1.11; b = 11.55; c = 12.78.Discussion Management of cerebral edema in patients with FHF depends on objective measurements of CPP or ICP, even though empiric therapy for ICP can be initiated without knowing ICP value. The goal is to keep CPP >40-50 mm Hg and ICP <30-40 mm Hg [4,9] no matter what the cause of the edema. During liver transplantation, however, patients are susceptible to sudden changes in ICP or CPP because of potential systemic hypotension and frequent changes in fluid balance and intravascular volume (blood loss, edema), venous pressures (clamping and unclamping of major vessels), overall hemodynamic stability (low contractility and peripheral vasodilation), and potential intracerebral bleeding (clotting abnormalities) [10-12]. ICP monitoring during orthotopic liver transplantation [6,7,12,13] provided evidence that ICP frequently increases in late Stage 2 and even more frequently in early Stage 3 (new liver perfusion) because of volume overload and postreperfusion cerebral hyperperfusion [13]. Thus, preoperative and intraoperative management is aimed at decreasing intracranial edema and pressure to control and maintain adequate brain perfusion. The options for ICP monitoring are placing a subdural, epidural, or intraventricular catheter; the latter is potentially more useful because of the therapeutic ability to withdraw cerebrospinal fluid. However, it has a higher associated risk for intracerebral bleeding. Placing a subdural catheter may carry less risk; however, it is an invasive procedure as well, and requires expert surgical technique--especially in those patients with coagulopathy who are susceptible to intracranial bleeding [6,8]. An alternative mode of monitoring is TCD, which has been used extensively for monitoring of head injury and cerebral circulatory arrest [14] and has been studied extensively in head-trauma patients [15]. However, in a previous report of three patients with FHF and brain edema, TCD monitoring failed to show any abnormal findings before liver transplantation [16], as we did in our patient. Even though ICP and computed tomography findings did not correlate well in a large series of patients [10,17] ICP monitoring is still considered the best method to evaluate and treat brain perfusion in patients with increased ICP, as well as prevent adverse neurologic outcome. Thus, the value of TCD will, in part, be determined by comparing TCD with ICP monitoring (as demonstrated in our patient). The extensive studies of TCD monitoring in head trauma patients have contributed some information about the relationship between ICP and TCD. Diastolic FV is influenced by cerebral vascular resistance, which is determined mainly by ICP and vessel diameter [15]. TCD images show that diastolic FV becomes hero when ICP equals diastolic blood pressure [18]. This is a conclusive warning sign, at which time TCD images of the diastolic component should be compared with diastolic blood pressure (rather than systolic or mean pressure). PI (difference between systolic and diastolic FV divided by mean FV), which also represents resistance to flow, can be correlated with ICP [15] or CPP (mean blood pressure--ICP) [19] in head-trauma patients. This correlation, however, has been weak [20], individual [15], or confounded when investigated in patients with multiple pathologic subgroups (diffuse, focal, hyperemic lesions) with minimal data derived from each pathology [19]. We think that PD (the difference between systolic and diastolic FV) is an easy variable to calculate and represents the same resistance to flow that PI describes; however, it has never before been correlated with ICP or CPP. Various experimental [21], laboratory and studies however, that the Doppler can resistance information that can be related to ICP or FV during or of was about three with and of of the This is by partial of the or by and decreased velocity The can be in of a PI = systolic - diastolic FV = total in FV divided by the of the mean flow a During increased ICP mm Hg), is a increase in pulsatility difference) of FV sudden increase in systolic FV and sudden decrease in diastolic FV), to a intracranial artery pressure, and to the that become The PI a measure to describe the of but other FV parameters can be used to peripheral flow systolic [21], diastolic or mean FV the the and resistance index = systolic - diastolic FV) However, all the other parameters are considered less when high ICP and total cerebral resistance A TCD FV (including and even though frequent to may a is the for for a and more variable to We think that calculation of FV pulsatility FV) difference resistance in a similar to PI or with the of and which the indices are We also that it is more to the relationship between TCD and which represents perfusion pressure, rather than ICP, which may not systemic blood pressure or of perfusion ICP measurement does have value in its right in of However, any previous to demonstrate correlation between cerebral FV and cerebral pressure showed that CPP is a better compared with ICP when cerebral O2 and O2 parameters are during brain injury A better correlation with PI and PD Table 1 is to CPP of perfusion pressure rather than intracerebral is that when ICP is high it is to be the in brain more than the ability to perfusion but that only when is and mm Hg or mean CPP mm Hg), and any increase in flow or cerebral perfusion also increase brain volume and ICP. we were in the before is ICP was not the with which to we that it may be to "diastolic" CPP (diastolic blood pressure--ICP) with TCD diastolic or TCD PD because of the relationship between TCD diastolic and diastolic blood pressure [18]. We that PD was when diastolic CPP was mm Hg, which is to a mean CPP of mm Hg Figure 4 and Figure This is a of resistance and its relationship with CPP or ICP. The correlation of resistance by with CPP change according to ICP mm Hg, between and mm Hg, and mm or CPP mm Hg where is between and mm Hg, which is a mm Hg where is The increase in resistance in 3 is to an increase in the of during each rather than an increase in venous resistance and this change in relationship in 2 and 3 is in the of the overall relationship polynomial between PD and CPP or between PI and CPP when mean CPP <50 mm Hg Figure 5, A and B. However, at that to diastolic CPP PD may have a to increase cerebral blood volume and perfusion be increased ICP and O2 are still high (i.e., during Stage 3 of liver with and status be induced (exponential relationship in Figure 4 and Figure On the other PD is to decrease perfusion pressure with and mean blood pressure (= all low O2 is still high Also, the of blood pressure systemic on FV and resistance is similar to the relationship of CPP to three an with relationship and a TCD imaging provided adequate comparable to that derived from ICP monitoring, when cerebral perfusion was low Figure 2 and Figure 4. was an inverse relationship between "diastolic" CPP and TCD PD (r = for 29 of Figure low perfusion pressure or high resistance by well with CPP mm Hg or diastolic CPP <30-40 mm Hg Figure 4. correlation, even though it is derived from one is comparable to that derived from studies of head injury r of for a of PI with ICP or r = for a with CPP. In our the recording decreased to each time CPP decreased to Figure Even though in some of decreased CPP (mean CPP <50 mm decreased to cm/s Figure 2 and PI increased to cm/s Figure 3, PD increased in all to cm/s Figure 2 and Figure A decrease in CPP by TCD or ICP monitoring was treated to increase systemic pressure and decrease ICP when treatment decreased PD to <50 cm/s Figure or high TCD PD were diagnosed and treated and only and the patient was normal A previous report showed that PI was when CPP became mm Hg [19]. this is a of the relationship between CPP and TCD pulsatility or our data from one patient that similar acute changes in the of the relationship can at cm/s PD Figure 4 to CPP <50 mm Hg or diastolic CPP mm Hg), which may high flow resistance and low perfusion in the The of patients with FHF and Grade 4 encephalopathy during liver transplantation may be by cerebral perfusion monitoring. as that from our that the use of TCD monitoring is and that a is to demonstrate the relationship between brain perfusion by and intracranial pressures during brain edema. Also, studies should between cerebral as to a more studies should the of a an acute or a in TCD and CPP relationship can be used to low cerebral perfusion. After establishing a relationship in a laboratory a of ICP TCD monitoring should be to demonstrate therapeutic and with decreased