Dorsal Root Ganglion Stimulation Relieves Chronic Neuropathic Pain Along With a Decrease in Cortical γ Power.

BACKGROUND: Stimulation of dorsal root ganglion (DRG) is an ideal neuromodulative intervention, providing pain relief in localized chronic pain conditions because γ-band oscillations reflect the intensity of ongoing chronic pain in patients affected. OBJECTIVE: We aimed to observe the role of cortical γ-band power associated with the relief of chronic neuropathic pain through DRG stimulation (DRGS). MATERIALS AND METHODS: We examined nine patients (two women, mean age 56.8 years; range, 36-77 years) diagnosed with chronic neuropathic pain who underwent DRGS therapy. We used the numeric rating scale (NRS) on the painful limb and simultaneously recorded the electroencephalography to assess the broadband γ power. Assessments were conducted on the first day and on the seventh day after implantation of the DRGS system and then compared and correlated with the results of the NRS. RESULTS: The NRS scores showed a significant decrease from the first day to the seventh day (p = 0.007). The resting-state γ power revealed a significant decrease (p = 0.021) between 30 and 45 Hz, recorded through the central electrode contralateral to the painful limb from the first day (mean [M] = 0.46, SD = 0.25) to the seventh day (M = 0.31, SD = 0.12) after DRGS. There was no significant change in the resting-state γ-band power recorded through the central electrode ipsilateral to the painful limb. However, we found a positive correlation in the γ-band power (rs = 0.628, p = 0.005) with the NRS rating. CONCLUSIONS: A lateralized decrease in broadband γ power may be considered further evidence supporting a reduction in the hyperexcitability of the nociceptive system in response to DRGS therapy. In the future, γ-band power could serve as a biomarker for assessing the efficacy of DRGS during the seven-day test phase preceding the implantation of the DRGS system.

Is it possible to generate an additional pleasant and pain-relieving muscle stimulation when using a low-frequency spinal cord stimulation (SCS) for the treatment of lower back pain? Pilot study: A new technique: "MuscleSCS".

OBJECTIVE: The combined use of spinal cord stimulation (SCS) and muscle stimulation, in the treatment of chronic pain, using the same probe, could improve the clinical results. However, this technique has not been established as yet. It was our hypothesis that it is possible to generate muscle stimulation by using low frequencies with SCS electrodes and use it to additionally treat chronic back pain. METHODS: We generated muscle stimulation in patients with previously implanted SCS electrodes, for the treatment of lower back pain, by using low frequencies (2, 4, 6, and 8 Hz) and different contact combinations of the electrodes. The results were evaluated by using visual inspection (videos), haptic control, surface electromyography (EMG), and sonographic recordings. RESULTS: This pilot study (17 patients, seven females, age 36-87 years, 11 percutaneous paddle leads, and 6 octrodes) was performed at the Neurosurgical Department of the University of Tuebingen. The most preferred frequencies were 6 Hz (45.5% of percutaneous paddle leads) and 8 Hz (50% of octrodes) at contacts 3&4 or 5&6. The preference of frequencies differed significantly among genders (p = 0.023). Simultaneous EMG and ultrasonic recordings demonstrated the generation of muscle potentials and the stimulation of deeper muscle groups. CONCLUSION: In this study, it has been shown that with low-frequency SCS stimulation, pleasant and pain-relieving muscle contractions of the lower and upper back can also be generated. This combined method has been coined by us as "MuscleSCS" technique. Clinical trials are necessary to establish the value of this combined technique and its subtypes.

[Surgical procedures for treatment of spasticity]. / Chirurgische Verfahren zur Therapie von Spastik.

BACKGROUND: The causes of spasticity are various and include cerebral palsy, spinal cord injury, stroke, multiple sclerosis or other congenital or acquired lesions of the central nervous system (CNS). While there is often a partial functional component, spasticity also results in varying degrees of impairment of the quality of life. OBJECTIVE: A review of surgical treatment options for spasticity. MATERIAL AND METHODS: A systematic PubMed review of the literature on epidemiology and treatment options with a focus on neurosurgical interventions for spasticity and developments in the last 20 years as well as inclusion of still valid older landmark papers was carried out. Illustration of indications, technique, follow-up, and possible pitfalls of the different methods for the surgical treatment of spasticity. RESULTS: Depending on the affected region, the number of muscle groups, and the extent of spasticity, focal (selective peripheral neurotomy, nerve transfer), regional (selective dorsal rhizotomy), or generalized (baclofen pump) procedures can be performed. The indications are usually established by an interdisciplinary team. Conservative (physiotherapy, oral medications) and focally invasive (botulinum toxin injections) methods should be performed in advance. In cases of insufficient response to treatment or only short-term relief, surgical methods can be evaluated. These are usually preceded by test phases with, for example, trial injections. CONCLUSION: Surgical methods are a useful adjunct in cases of insufficient response to conservative treatment in children and adults with spasticity.

Laser-evoked potentials recover gradually when using dorsal root ganglion stimulation, and this influences nociceptive pathways in neuropathic pain patients.

OBJECTIVE: Dorsal root ganglion stimulation (DRGS) is able to relieve chronic neuropathic pain. There seems evidence that DRGS might achieve this by gradually influencing pain pathways. We used laser-evoked potentials (LEP) to verify our hypothesis that the recovery of the LEP may reflect DRGS-induced changes within the nociceptive system. METHODS: Nine patients (mean age 56.8 years, range 36-77 years, two females) diagnosed with chronic neuropathic pain in the knee or groin were enrolled in the study. We measured each patient's LEP at the painful limb and contralateral control limb on the first, fourth, and seventh day after implantation of the DRGS system. We used the numeric rating scale (NRS) for the simultaneous pain assessment. RESULTS: The LEP amplitude of the N2-P2 complex showed a significant increase on day 7 when compared to day 1 (Z = -2.666, p = 0.008) and to day 4 (Z = -2.547, p = 0.011), respectively. There was no significant difference in the N2-P2 complex amplitude between ON and OFF states during DRGS. The patients' NRS significantly decreased after 1 day (p = 0.007), 4 days (p = 0.007), and 7 days (p = 0.007) when compared to the baseline. CONCLUSIONS: The results show that with DRGS, the LEP recovered gradually within 7 days in neuropathic pain patients. Therefore, reduction of the NRS in patients with chronic neuropathic pain might be due to DRGS-induced processes within the nociceptive system. These processes might indicate neuroplasticity mediated recovery of the LEP.

Effectiveness and Safety of Dorsal Root Ganglion Stimulation for the Treatment of Chronic Pain: A Pooled Analysis.

INTRODUCTION: Since it became available in the mid-2010s, dorsal root ganglion (DRG) stimulation has become part of the armamentarium to treat chronic pain. To date, one randomized controlled trial, and several studies of moderate sample size and various etiologies have been published on this topic. We conducted a pooled analysis to investigate the generalizability of individual studies and to identify differences in outcome between chronic pain etiologic subgroups and/or pain location. MATERIALS AND METHODS: One prospective, randomized comparative trial and six prospective, single-arm, observational studies were identified that met pre-defined acceptance criteria. Pain scores and patient-reported outcome (PRO) measures were weighted by study sample sizes and pooled. Safety data are reported in aggregate form. RESULTS: Our analysis included 217 patients with a permanent implant at 12-month follow-up. Analysis of pooled data showed an overall weighted mean pain score of 3.4, with 63% of patients reporting ≥50% pain relief. Effectiveness sub-analyses in CRPS-I, causalgia, and back pain resulted in a mean reduction in pain intensity of 4.9, 4.6, and 3.9 points, respectively. Our pooled analysis showed a pain score for primary affected region ranging from 1.7 (groin) to 3.0 (buttocks) and responder rates of 80% for foot and groin, 75% for leg, and 70% for back. A substantial improvement in all PROs was observed at 12 months. The most commonly reported procedural or device complications were pain at the IPG pocket site, lead fracture, lead migration, and infection. CONCLUSIONS: DRG stimulation is an effective and safe therapy for various etiologies of chronic pain.

Characterization of traumatic spinal cord injury model in relation to neuropathic pain in the rat.

Purpose/aim: Neuropathic pain following spinal cord injury (SCI) has a tremendous impact on patient's quality of life, and frequently is the most limiting aspect of the disease. In view of the severity of this condition and the absence of effective treatments, the establishment of a reliable animal model that reproduces neuropathic pain after injury is crucial for a better understanding of the pathophysiology and for the development of new therapeutic strategies. Thus, the objective of the present study was to standardize the traumatic SCI model in relation to neuropathic pain. MATERIALS AND METHODS: Wistar rats were submitted to SCI of mild intensity (pendulum height 12.5 mm) or moderate intensity (pendulum height 25 mm) using the New York University Impactor equipment. Behavioural assessment was performed during 8 weeks. Thereafter, spinal cords were processed for immunohistochemistry. RESULTS: The animals of the moderate injury group in comparison with mild injury had a greater motor function deficit, worse mechanical allodynia, and latter bladder recovery; moreover, histological analysis revealed more extensive lesions with lower neuronal population. CONCLUSIONS: Our study suggests that moderate SCI causes a progressive and long-lasting painful condition (at least 8 weeks), in addition to motor impairment, and thus represents a reliable animal model for the study of chronic neuropathic pain after SCI.

Neurophysiological Effects of Dorsal Root Ganglion Stimulation (DRGS) in Pain Processing at the Cortical Level.

OBJECTIVES: Dorsal root ganglion stimulation (DRGS) has been used successfully against localized neuropathic pain. Nevertheless, the effects of DRGS on pain processing, particularly at the cortical level, remain largely unknown. In this study, we investigated whether positive responses to DRGS treatment would alter patients' laser-evoked potentials (LEP). METHODS: We prospectively enrolled 12 adult patients with unilateral localized neuropathic pain in the lower limbs or inguinal region and followed them up for six months. LEPs were assessed at baseline, after one month of DRGS, and after six months of DRGS. Clinical assessment included the Numerical Rating Scale (NRS), Brief Pain Inventory (BPI), SF-36, and Beck Depression Inventory (BDI). For each patient, LEP amplitudes and latencies of the N2 and P2 components on the deafferented side were measured and compared to those of the healthy side and correlated with pain intensity, as measured with the NRS. RESULTS: At the one- and six-month follow-ups, N2-P2 amplitudes were significantly greater and NRS scores were significantly lower compared with baseline (all p's < 0.01). There was a negative correlation between LEP amplitudes and NRS scores (rs = -0.31, p < 0.10). CONCLUSIONS: DRGS is able to restore LEPs to normal values in patients with localized neuropathic pain, and LEP alterations are correlated with clinical response in terms of pain intensity.

Dorsal Root Ganglion Stimulation Used for the Treatment of Chronic Neuropathic Pain in the Groin: A Single-Center Study With Long-Term Prospective Results in 34 Cases.

OBJECTIVE: Chronic neuropathic pain in the groin is a severe condition and difficult to treat. Dorsal root ganglion stimulation (DRGS) covers discrete painful areas precisely with its stimulation power in comparison to spinal cord stimulation (SCS). It was our hypothesis that DRGS provides a long-term relief of chronic groin pain over a period of more than three years. MATERIALS AND METHODS: Patients (age >18 years) with chronic neuropathic groin pain were prospectively examined. After a successful test-trial (duration of 3-10 days, pain decrease >50%) a permanent generator was implanted. The patients were re-examined after three months, then after one year, two, and three years. We used the Visual Analogue Scale (VAS), the Pain Disability Index (PDI), the Pain Catastrophizing Scale (PCS), the Brief Pain Inventory (BPI), and the Beck Depression Inventory (BDI) for the assessment. RESULTS: We included 34 consecutive patients (13 female, 21 male, mean age 50.4 years, range of age 24-84 years, 30/34 trial to permanent conversion) during the time period from 2012 until 2016. Thirty patients had a successful test-trial and a generator was subsequently implanted. Results after three years: the preoperative VAS dropped from Mdn = 8 to Mdn = 4.5 (p = 0.001). The PDI decreased from Mdn = 48 to Mdn = 23 (p = 0.004). The PCS changed from Mdn = 31 to Mdn = 16 (p = 0.006). The BPI dropped from Mdn = 76 to Mdn = 30 (p = 0.003). The BDI decreased from Mdn = 17 to Mdn = 7 (p = 0.010). Five patients showed complications (16.7%). CONCLUSION: In this study, DRGS proved an efficient long-term method for the treatment of chronic neuropathic groin pain and we strongly recommend its use.

Noninvasive measurement of intracranial pressure via the pulsatility index on transcranial Doppler sonography: Is improvement possible?

PURPOSE: We hypothesized that using hemodynamic variables could improve the prediction of intracranial pressure (ICP) from the middle cerebral artery pulsatility index (PI) measured with transcranial Doppler sonography. METHODS: In this prospective study, 39 patients with traumatic brain injury were routinely examined with transcranial Doppler sonography, and the middle cerebral artery PI was calculated. A multivariate model including hematocrit, mean arterial blood pressure, heart rate, and arterial CO2 pressure (PaCO2 ) was evaluated. RESULTS: Thirty-nine comatose patients (16 women and 23 men; age range 18-73 years; median 44 years) were included, and 234 data pairs (consisting of ICP and corresponding PI values) were analyzed. ICP ranged from -3 mmHg to +52 mmHg, and PI from 0.6 to 2.85. We found a significant but weak correlation between PI and the square root of ICP (R(2) between 0.29 and 0.34, p < 0.0001). A slightly stronger correlation was detected when hemodynamic variables were incorporated (R(2) between 0.37 and 0.43). Of these variables, mean arterial blood pressure had the most significant influence. CONCLUSIONS: In this study, PI was not a sufficiently strong predictor of ICP to be used in clinical practice. Its reliability did not improve even when hemodynamic variables were considered. Therefore, we recommend abandoning the use of PI for the noninvasive measurement of ICP in clinical practice.

Combined spinal cord and peripheral nerve field stimulation for persistent post-herniorrhaphy pain.

OBJECTIVES: Chronic post-hernia pain is a common complication after inguinal herniorrhaphies. Peripheral nerve field stimulation (PNFS) and spinal cord stimulation (SCS) are two new promising treatment modalities. Four patients with persistent neuropathic post-hernia pain were recruited for this prospective study. MATERIALS AND METHODS: Electrodes were inserted into the epidural space of the spinal canal and into the subcutaneous tissue in the inguinal region during a single surgical procedure. During a 14-day trial, double-blind stimulation was performed via an external stimulator: three days using the spinal electrode (SCS), three days using the inguinal electrode (PNFS), three days using both (SCS + PNFS), and five days off, with an alternating order from patient to patient. During the trial, pain intensity was assessed thrice daily by the visual analog scale. Additionally, pain intensity and quality of life (QOL) were assessed before and after surgical intervention by the Brief Pain Inventory, SF36 scale, and Pain Disability Index. RESULTS: All patients had a marked pain reduction during the trial phase, and this reduction was more prominent when both electrodes were activated simultaneously (p < 0.001). At the late follow-up, a significant pain reduction and improvement of QOL was observed in three patients. CONCLUSIONS: Both SCS and PNFS are effective in treating post-hernia pain, but the magnitude of pain reduction was more prominent with concomitant stimulation. Combined PNFS and SCS should be considered for patients with a less than optimal response to either SCS or PNFS. More studies are necessary to address the cost-effect issues of this new approach to treatment.

Experimental comparison of the measurement accuracy of the Licox(®) and Raumedic (®) Neurovent-PTO brain tissue oxygen monitors.

BACKGROUND: Only a few experimental reports are available on the direct comparison of Licox(®) and Raumedic(®)-Neurovent-PTO brain tissue oxygen pressure (P(br)O(2)) monitors. We compared the two systems regarding their measurement properties under experimental in vitro and in vivo conditions. MATERIALS AND METHODS: Eight Licox(®) and Raumedic(®) Neurovent-PTO(®) sensors were tested for 10 min at 37°C, atmospheric pressure, at an oxygen content of 0% and 100% before and after the in vivo test. The same probes were implanted in German landrace pigs, which underwent hepatectomy. The mean P(br)O(2) values were recorded every minute. An O(2) challenge with inhalation of 100% O(2) for 10 min was performed 2 h post-abdominal surgery. RESULTS: At 0% O(2) content values varied from 0.2 to 7 mmHg, at 100% O(2) content from 130 to 165 mmHg. No difference between probes was found. In vivo tests: Raumedic® showed higher P(br)O(2) values (mean +6.3 mmHg, p < 0.0001) compared with Licox®. During O(2) challenge, both probes responded similarly; however, Raumedic(®) had a 10% higher response amplitude (p < 0.005). After explantation there was again no difference between the two sensors. CONCLUSION: Raumedic(®) sensors measured higher P(br)O(2) values. There was no significant difference regarding overall measurement of in vitro accuracy between the two probes, which proved to be robust when used consecutively for longer periods and in different environments.

Is P(br)O (2) pressure reactivity index (ORx) dependent on the type of oxygen probe? An in vivo study.

OBJECTIVE: To evaluate if ORx is dependent on the type of brain tissue O(2) (P(br)O(2)) probe in an in vivo setting. METHODS: In eight German landrace pigs two types of probes were implanted simultaneously in the same cerebral hemisphere. All pigs underwent hepatectomy and received neuromonitoring until death. A LICOX(®) probe CCI.S, representing a Clarke type electrode, was compared with a Raumedic Neurovent PTO, representing an optode. Data were sampled at 50 Hz. Average values were calculated every 30 s. Cerebral perfusion pressure (CPP) was averaged over 30 s. ORx was calculated for each probe. To increase the signal to noise ratio of the ORx, the ORx values, which had been assessed every minute, were averaged over 1 h. RESULTS: The overall measurement time was 145.1 h (8,703 data pairs). Despite a mean difference of 6.2 mmHg (p < 0.0001) in the measured values of P(br)O(2), the mean ORx(licox) was 0.139, mean ORx(raumedic) 0.146 (p = 0.2098). Correlation coefficient of ORx values assessed every minute and every hour was 0.52 and 0.58 respectively. CONCLUSION: Despite this significant difference in absolute values of P(br)O(2) the derived mean ORx values were not different. Similar to the established Licox system, the Raumedic system seems to enable a valid ORx recording.

Correlation of the intracranial pressure to the central venous pressure in the late phase of acute liver failure in a porcine model.

Volume loading is a common method used to ensure adequate circulation. However, in the late phase of acute liver failure complications that often lead to death are cerebral swelling and brainstem edema, which are considered to result from increasing intracranial pressure (ICP). In former studies cerebral venous pressure (CVP) and ICP were reported to be independent entities. Acute liver failure was induced in 25 German land race pigs by acetaminophen intoxication. CVP and ICP were measured continuously. Hydroxyethyl starch solution and noradrenalin were administered to stabilize the circulation at a mean arterial pressure above 60mmHg. There is an increasing correlation in quantity and quality between the CVP and ICP in the last 24 h before exitus. Beginning with a slope of 0.24 (ICP against CVP) and a low correlation coefficient of 0.08. 24h before exitus, this situation remained stable until 16 h to exitus (m = 0.22, r = 0.1). The correlation increased from 16 to 8 h prior to exitus to a slope of m = 0.5 and a correlation of r = 0.3 and remained until exitus. In late acute liver failure it seems therefore clinically reasonable to keep circulation within an adequate range by the use of noradrenalin and to avoid fluid overload.

The values of cerebrovascular pressure reactivity and brain tissue oxygen pressure reactivity in experimental anhepatic liver failure.

BACKGROUND: We investigated in a porcine model of anhepatic acute liver failure (ALF), the value of two parameters describing cerebrovascular autoregulatory capacity, pressure reactivity index (PRx) and brain tissue oxygen pressure reactivity (ORx), regarding their power to predict the development of intracranial hypertension. METHODS: In six pigs, hepatectomy was performed. Only one animal was sham operated. All animals received neuromonitoring including arterial blood pressure, intracranial pressure (ICP), and brain tissue partial oxygen pressure (P(br)O(2)). The average time of neuromonitoring was 31.0 h. Cerebral perfusion pressures (CPP), cerebrovascular pressure reactivity index (PRx) and brain tissue oxygen reactivity index (ORx) were calculated. RESULTS: Perioperative disturbance of AR improved within 4 h after surgery. From 6 to 16 h post hepatectomy, ICP did slowly increase by 4 mmHg from baseline; CPP remained stable around 40 mmHg. PRx and ORx, however, indicated in this period a progressive loss of AR, reflected in a decrease of P(br)O(2) despite unchanged CPP. Beyond 16 h, ICP rose quickly. At CPP levels below 35 mmHg, P(br)O(2) fell to ischemic levels. CONCLUSIONS: The loss of cerebrovascular autoregulatory capacity, indicated by a rise of PRx and ORx precedes the final crisis of uncontrollable intracranial hypertension in this animal model by hours. During this phase cerebral blood flow, as reflected in tissue oxygenation, deteriorates despite unchanged CPP. Monitoring of AR during ALF therefore seems to carry the power to identify a risk for development of critical CBF and intracranial hypertension.

Analysis of Somatosensory Profiles Using Quantitative Sensory Testing During Tonic and BurstDR Stimulation for the Treatment of Chronic Pain.

BACKGROUND: In the presence of neuropathic pain, other sensory qualities, such as touch or pressure, which are a sign of nerve damage, are almost always affected. However, it is unclear to which extent spinal cord stimulation (SCS) influences these simultaneously damaged sensory pathways or possibly contributes to their regeneration. OBJECTIVES: The aim of this study was to investigate the effects and possible differences of tonic and BurstDR (Abbott, Austin, TX) SCS on somatosensory profiles of patients with chronic neuropathic pain, using quantitative sensory testing (QST). STUDY DESIGN: A randomized, single-blinded, single-center study. SETTING: University medical center. METHODS: After a washout phase of 4 hours and having done the basic QST measurement, either tonic or BurstDR stimulation was performed for 30 minutes in a randomized fashion. Then, the second measurement was taken. The third measurement followed after using the remaining stimulation mode for 30 minutes. Mean values of all QST parameters were calculated and compared. We also computed Z-values using standard data. RESULTS: We examined 14 patients (9 women, 5 men, mean age 58.4 years) with previously implanted SCS systems for chronic neuropathic pain, using QST (7 tests, 13 parameters).The QST raw data showed a statistically significant improved vibration sensation (A-Beta) (P = 0.019) and lower mechanical pain threshold (A-Delta) (P = 0,031) when testing BurstDR in comparison to tonic SCS. We found a significant improvement in the vibration sensation and also A-Beta fiber function during BurstDR when we used the Z-value analysis (P = 0.023). With regard to Z-values, BurstDR seemed to be superior regarding the normalization tendency of the A-Delta fiber function in the mechanical pain threshold (P = 0.082), and tonic SCS seemed superior regarding heat detection threshold (C) and cold pain threshold (C and A-Delta) (P = 0.093). LIMITATIONS: The study is limited by its small number of cases. CONCLUSIONS: In this study, it could be shown that, in some QST parameters and tested fiber functions, normalization tendencies were recognizable by using BurstDR or tonic SCS. However, BurstDR SCS seemed to be superior to tonic stimulation in this regard.

Influence of Spinal Cord Stimulation on Insulin Sensitivity in Chronic Pain Patients.

BACKGROUND AND OBJECTIVE: This prospective, sham-controlled, randomized, cross-over study (NCT03637075), was designed to test the hypothesis that spinal cord stimulation (SCS) for the treatment of pain can also improve glucose metabolism and insulin sensitivity when compared to sham stimulation. METHODS: Ten non-diabetic participants (5 females, mean age 48.8 years) who had an SCS system implanted for the treatment of chronic neuropathic pain were studied. Whilst applying a hyperinsulinemic-euglycemic clamp, sham-stimulation and tonic stimulation were performed for 45 min (n=4) or 60 min (n=6) in each case randomly. The insulin sensitivity index and pain levels were determined. A second investigation, BurstDR stimulation was also conducted and the result was compared to that of sham stimulation (cross-over design). RESULTS: The insulin sensitivity improved significantly under the tonic stimulation when compared to the sham stimulation (p=0.037). BurstDR stimulation independently did not lead to a significantly improved insulin sensitivity compared to that after sham stimulation (p=0.16). We also examined the pain during the test and found no significant difference between sham and tonic stimulation (p=0.687). CONCLUSION: The results of this study show that tonic stimulation used for the treatment of pain could also improve glucose metabolism and insulin sensitivity. Further investigations are required to investigate the clinical relevance of the role of glucose metabolism in diabetic chronic pain participants and its underlying mechanisms.

Early biomarkers predicting outcome in a porcine model of acetaminophen intoxication: A pilot study.

BACKGROUND: Acetaminophen intoxication has become the leading cause of acute liver failure (ALF) in Europe and the USA. OBJECTIVES: To identify early biomarkers in order to predict the development of ALF in a porcine model of acetaminophen intoxication. MATERIAL AND METHODS: Six German Landrace pigs received a single acetaminophen bolus of 1 g/kg body weight via a jejunal catheter. Cytokines and laboratory parameters were analyzed at 8-hour intervals for a total of 40 h. RESULTS: Three of the 6 animals survived the intoxication. The nonsurviving animals had an increase in serum lactate and interleukin (IL)-6, with a simultaneous decrease in prothrombin time (PT) and albumin concentration 8 h after intoxication. In all nonsurviving animals, elevated levels of tumor necrosis factor alpha (TNF-α) at baseline before intoxication and during the course of ALF were observed. The acetaminophen serum concentrations and toxicokinetics did not differ between the nonsurviving and surviving animals. Methemoglobinemia was proportional to the administered doses and acetaminophen blood levels, but methemoglobinemia did not affect survival. CONCLUSIONS: Tumor necrosis factor alpha, IL-6, lactate, prothrombin time, and albumin blood concentration were identified as early predictors of outcome after acetaminophen intoxication. An elevated TNF-α level before acetaminophen exposure was the earliest prognostic marker for a lethal outcome. Therefore, it could serve as a very early indicator of prognosis.

A simple dummy liver assist device prolongs anhepatic survival in a porcine model of total hepatectomy by slight hypothermia.

BACKGROUND: Advances in intensive care support such as therapeutic hypothermia or new liver assist devices have been the mainstay of treatment attempting to bridge the gap from acute liver failure to liver transplantation, but the efficacy of the available devices in reducing mortality has been questioned. To address this issue, the present animal study was aimed to analyze the pure clinical effects of a simple extracorporeal dummy device in an anhepatic porcine model of acute liver failure. METHODS: Total hepatectomy was performed in ten female pigs followed by standardized intensive care support until death. Five animals (dummy group, n = 5) underwent additional cyclic connection to an extracorporeal dummy device which consisted of a plasma separation unit. The separated undetoxified plasma was completely returned to the pigs circulation without any plasma substitution or exchange in contrast to animals receiving intensive care support alone (control group, n = 5). All physiological parameters such as vital and ventilation parameters were monitored electronically; laboratory values and endotoxin levels were measured every 8 hours. RESULTS: Survival of the dummy device group was 74 ± 6 hours in contrast to 53 ± 5 hours of the control group which was statistically significant (p < 0.05). Body temperature 24 hours after hepatectomy was significantly lower (36.5 ± 0.5°C vs. 38.2 ± 0.7°C) in the dummy device group. Significant lower values were measured for blood lactate (1.9 ± 0.2 vs. 2.5 ± 0.5 mM/L) from 16 hours, creatinine (1.5 ± 0.2 vs. 2.0 ± 0.3 mg/dL) from 40 hours and ammonia (273 ± 122 vs. 1345 ± 700 µg/dL) from 48 hours after hepatectomy until death. A significant rise of endotoxin levels indicated the onset of sepsis at time of death in 60% (3/5) of the dummy device group animals surviving beyond 60 hours from hepatectomy. CONCLUSIONS: Episodes of slight hypothermia induced by cyclic connection to the extracorporeal dummy device produced a significant survival benefit of more than 20 hours through organ protection and hemodynamic stabilisation. Animal studies which focus on a survival benefit generated by liver assist devices should especially address the aspect of slight transient hypothermia by extracorporeal cooling.

Standardized intensive care unit management in an anhepatic pig model: new standards for analyzing liver support systems.

INTRODUCTION: Several anhepatic pig models were developed in the past. Most models suffer from short anhepatic survival times due to insufficient postoperative intensive care unit (ICU) management. The aim of this study was to analyze anhepatic survival time under standardized intensive care therapy in a pig model. METHODS: Eight pigs underwent total hepatectomy after Y-graft interposition between the infrahepatic vena cava and the portal vein to the suprahepatic vena cava. An intracranial probe was inserted for intracranial pressure (ICP) monitoring. Animals received pressure-controlled ventilation under deep narcosis. Vital parameters were continuously recorded. Urinary output, blood gas analysis, haemoglobin, hematocrit, serum electrolytes, lactate, and glucose were monitored hourly, and creatinine, prothrombin time, international normalised ratio, and serum albumin were monitored every 8 hours. Sodium chloride solution 0.9%, hydroxyethyl starch 6%, fresh frozen plasma, and erythrocyte units were used for volume substitution, and norepinephrine was used to prevent severe hypotension. Serum electrolytes and acid-base balance were corrected as required. Antibiotic prophylaxis with ceftriaxon was given daily, as well as furosemide, to maintain diuresis. RESULTS: Postoperative survival was 100% after 24 hours, with a maximum survival of 73 (mean, 58 ± 4) hours. Haemodynamic parameters such as heart rate, mean arterial pressure, and pulse oximetry remained stable during surgical procedures and following anhepatic status due to ICU therapy until escalating at time of death. Deteriorating pulmonary function could be stabilized by increasing oxygen concentration, positive end-expiratory pressure, and maximal airway pressure. Furosemide was used to maintain diuresis until renal failure occurred. ICP started at 15-17 mmHg and increased continuously up to levels of 41-43 mmHg at time of death. All animals died as a result of multiple-organ failure. CONCLUSIONS: Using standardized intensive care management after total hepatectomy, we were able to prolong anhepatic survival over 58 hours without the use of liver support systems. The survival benefit of liver support systems in previous animal studies should be reevaluated against our model.