Iwona Bonney

Altered hematologic profiles following donor right hepatectomy and implications for perioperative analgesic management

Living liver donors for adult liver transplant recipients undergo extensive liver resection. Partial donor hepatectomies may alter postoperative drug metabolism and hemostasis; thus, the risks and the benefits of pain management for this unique patient population may need to be reassessed. The safety and efficacy of combined epidural analgesia and field infiltration in our initial living liver donor group are presented. A thoracic epidural catheter was placed before general anesthesia in 2 female and 6 male donors (44.2 ± 11.3 years old, mean ± standard deviation [SD], range 26–56). At the end of surgery, incisions were infiltrated (bupivacaine 0.25%), and an epidural infusion was used (bupivacaine 0.1% + hydromorphone hydrochloride 0.02%). Clinical outcomes were followed for 5 days. The time sequence of pain intensity on a 0–10 visual analog scale clustered into 3 phases, the intensity of which differed significantly from each other (2.2 ± 0.6, 0.69 ± 0.2, and 2.37 ± 0.3 respectively, P = 0.028). Right shoulder pain was observed in 75% of the donors. Sedation, pruritus, and nausea were minimal. Consistently maximal international normalized ratio elevation occurred at 17.6 ± 7 hours postoperatively, then slowly declined. Platelet counts were lowest on day 3. No neurologic injury or local anesthetic toxicity was observed. This 2‐site approach provided effective, safe, postoperative analgesia for our donors. Universally, coagulopathy ensued, indicating a potentially increased risk for epidural hemorrhage at epidural catheter removal and mandating close postoperative neurologic and laboratory monitoring. Research is needed to advance the understanding of postoperative coagulopathy and hepatic dysfunction in these donors to further optimize their perioperative management, including that of analgesia. (Liver Transpl 2004;10:363–368.)

Intrathecal antinociceptive interaction between the NMDA antagonist ketamine and the opioids, morphine and biphalin

Biphalin is an opioid peptide analogue that currently is under clinical development as a new type of site‐directed analgesic. In rats, the intrathecal (i.t.) analgesic potency of biphalin is 1000‐fold greater than morphine. Such a high activity may reflect this compounds activation of three types of opioid receptors (μ, δ and κ). NMDA receptors also play an important role in nociceptive processing. Therefore, we investigated in rats whether an NMDA antagonist may influence biphalin‐induced antinociception. In the present study, ketamine was chosen because of the widespread safe use of this drug in clinical practice. I.t. application of ketamine alone had relatively little analgesic effect and its excitatory effects limited possible doses of the drug. Co‐administration of ketamine with biphalin or morphine produced markedly greater antinociception than biphalin or morphine alone in acute, thermal tail flick testing. These results suggest that NMDA antagonists may be useful potentiators of biphalin analgesia. Thus, to obtain the same spinal antinociceptive effect, lower doses of biphalin or morphine are required when ketamine is co‐administered.

Endomorphins interact with tachykinin receptors.

Soon after the discovery of endomorphins several studies indicated differences between pharmacological effects of endomorphins and other MOR selective ligands, as well as differences between the effects of endomorphin I and endomorphin II. We now propose that these differences are the result of an additional non-opioid property of endomorphins, namely, their weak antagonist properties with respect to tachykinin NK1 and NK1 receptors.

Corticotropin-releasing hormone (CRH) produces analgesia in a thermal injury model independent of its effect on systemic beta-endorphin and corticosterone

To determine separately the effect of corticotropin-releasing hormone (CRH) on analgesia and on inflammation, rats were assigned to receive CRH 60 microg/kg, CRH 300 microg/kg, morphine 4 mg/kg, or normal saline intravenously 15 min before a burn injury. Two mesh chambers that allowed collection of fluid had been previously implanted subdermally in each rat. The skin overlying the right chamber was subject to thermal injury. The left chamber served as a control. We assessed systemic analgesia, and levels of beta-endorphin and corticosterone in plasma and in chamber fluid before, 1, 4 and 24 h after drug administration. The CRH groups exhibited longer tail flick latencies than the control group (P=0.0001) although the increase in latency was of smaller magnitude than in the morphine group. We did not observe a CRH dose response for analgesia. Plasma corticosterone levels were higher in the CRH 300 microg/kg group than in the normal saline group at 4 h (P=0.03). Levels of beta-endorphin in plasma as well as the levels of corticosterone and beta-endorphin in chambers were similar in the CRH 300 microg/kg group and in the normal saline group (all P values>0.1). Thus, systemically administered CRH produces analgesia in thermal injury independent of its effect on these two markers of local or systemic inflammation.

Sodium Homeostasis During Liver Transplantation and Correlation with Outcomes

BACKGROUND:Reports of perioperative serum sodium increase in liver transplant (LT) recipients are mostly restricted to unintentional rapid serum sodium overcorrection with subsequent development of central pontine myelinolysis. We examined intraoperative serum sodium changes and their effect on short-term outcomes after LT. METHODS:We retrospectively analyzed data of all LT recipients over a period of 3.5 years. Collected information included preoperative and postoperative serum sodium (Napre and Napost), delta sodium (&Dgr;Na), intraoperative serum sodium peak and trough with corresponding maximum &Dgr;Na, intraoperative peak blood glucose, history of hepatic encephalopathy, perioperative diuretics, intraoperative administration of vasopressin, dopaminergic agents, alkalizing drugs (sodium bicarbonate [NaHCO3], tromethamine), crystalloids, colloids, fresh frozen plasma (FFP), and packed red blood cells (PRBC). The delta of serum osmolality (&Dgr;Osm) was calculated from Napre and Napost, blood urea nitrogen, and blood glucose values, and the correlation between &Dgr;Na and &Dgr;Osm was examined. Outcomes analyzed included intubation for ≥2 days, postanesthesia care unit/surgical intensive care unit (PACU/SICU) length of stay (LOS) for ≥2 days, need of SICU admission, hospital LOS, postoperative neurological complications, and mortality. Univariate and multivariate analyses were performed to test associations between &Dgr;Na and outcomes. A P value <0.005 was considered significant. RESULTS:Data of 164 patients were analyzed. Their &Dgr;Na was 5.3 ± 4.5 (mean ± SD) mEq/L. A lower Napre was associated with greater &Dgr;Na, a relationship likely due to the regression to the mean. In a subgroup of patients with Napre < 130 mEq/L, &Dgr;Na was 11.0 ± 3.6 mEq/L, significantly higher than in normonatremic patients (P < 0.0001). Mortality and neurologic complications were not affected by changes in &Dgr;Na (all P ≥ 0.41). An increase in &Dgr;Na was associated with higher odds of prolonged intubation and prolonged PACU/SICU LOS in univariate and multivariate regression analyses (P = 0.0003 and P = 0.0049, respectively, for adjusted odds ratios). The odds ratios for associations of &Dgr;Na with those outcomes did not differ between patients treated versus not treated with NaHCO3. The intraoperative &Dgr;Na was significantly higher in patients with intraoperative hyperglycemia (P < 0.0001). Intraoperative administration of NaHCO3 and the number of transfused FFP and PRBC units were also associated with a significantly higher &Dgr;Na (P = 0.0001). The &Dgr;Na correlated significantly with &Dgr;Osm. CONCLUSIONS:A larger intraoperative increase in &Dgr;Na is associated with worse recipient short-term outcomes. Patients with preoperative hyponatremia may be at particular risk. &Dgr;Na increases with the intraoperative use of NaHCO3, quantity of FFP, and PRBCs transfused, as well as with intraoperative hyperglycemia. Potential differences on sodium homeostasis between NaHCO3 and tromethamine use for intraoperative pH adjustment should be prospectively investigated.

Antihyperalgesic effect of simultaneously released hydromorphone and bupivacaine from polymer fibers in the rat chronic constriction injury model.

We aimed to evaluate the antihyperalgesic efficacy of a combination of hydromorphone (HM) and bupivacaine (BP) delivered via controlled release from a biodegradable cylindrical rod. In vivo studies were performed using a rat model of thermal hyperalgesia induced by chronic constriction injury (CCI) of the sciatic nerve with loose ligatures. Poly(lactic-co-glycolic acid) (PLGA) rods (10 mm length, 1 mm diameter) loaded with HM (5 mg per rod), BP (5 mg per rod) or no drug (placebo) were implanted subcutaneously, in single or dual pairs, adjacent to the constriction injury, immediately after nerve ligation. We evaluated the efficacy of two dose levels for each drug, alone or in combination, in attenuating thermal hyperesthesia over a period of 12 days according to a prevention protocol. Plasma levels of drugs released from the rods and also released in an in vitro simulation were evaluated. In vitro studies demonstrated that drug release is maintained for at least 10 days. HM (5 mg) alone and BP (5 mg) alone did not attenuate hyperalgesia. Their combination provided a significant increase in the paw withdrawal latency as compared to single agents or placebo. When the dose in each group was doubled, implanting four rods, significant attenuation of hyperalgesia was observed. Analyses of rods retrieved after termination of experiments (after 12 days) revealed 30% residual HM and 70% residual BP content. Prolonged delivery of HM and BP alone or in combination via locally applied PLGA rods may offer a feasible alternative to provide long-lasting analgesia.

Availability of Anesthetic Effect Monitoring: Utilization, Intraoperative Management and Time to Extubation in Liver Transplantation

Titration of volatile anesthetics to anesthetic effect monitoring using the bispectral index (BIS) has been shown to decrease anesthetic requirements and facilitate recovery from anesthesia unrelated to liver transplantation (OLT). To determine whether availability of such monitoring influences its utilization pattern and affect anesthetic care and outcomes in OLT, we conducted a retrospective analysis in recipients with and without such monitoring. We evaluated annual BIS utilization over a period of 7 years, and compared 41 BIS-monitored patients to 42 controls. All received an isoflurane/air/oxygen and opioid-based anesthetic with planned postoperative ventilation. Data collection included age, body mass index (BMI), gender, Model for End-stage Liver Disease (MELD) score, and time to extubation (TtE). Mean preanhepatic, anhepatic, and postanhepatic end-tidal isoflurane concentrations were compared, as well as BIS values for each phase of OLT using the Kruskal-Wallis and Wilcoxon signed-rank tests, respectively. The use of anesthetic effect monitoring when available increased steadily from 15% of cases in the first year to almost 93% by year 7. There was no significant difference in age, gender, BMI, MELD, or TtE between groups. The BIS group received less inhalational anesthetic during each phase of OLT compared to the control group. However, this difference was statistically significant only during the anhepatic phase (P = .026), and was clinically not impressive. Within the BIS group, the mean BIS value was 38.74 ± 5.25 (mean ± standard deviation), and there was no difference for the BIS value between different transplant phases. Availability of anesthetic effect monitoring as an optional monitoring tool during OLT results in its increasing utilization by anesthesia care teams over time. However, unless integrated into an intraoperative algorithm and an early extubation protocol for fast tracking of OLT recipients, this utilization does not appear to provide a clinical benefit but instead drives cost.

Performance validation of a modified magnetic resonance imaging-compatible temperature probe in children

INTRODUCTION: During magnetic resonance imaging (MRI), children are at risk for body temperature variations. The cold MRI environment that preserves the MRI magnet can cause serious hypothermia. On the other hand, hyperthermia may also develop because of radiofrequency-induced heating of the tissues, particularly in prolonged examinations. Because of a lack of MRI-compatible core temperature probes, temperature assessment is unreliable, and specific absorption rate–related patient heat gain must be calculated to determine the allowable scan duration. We compared an MRI-compatible temperature probe and a modification thereof to a standard esophageal core body temperature probe in children. METHODS: Children undergoing general anesthesia were recruited, each patient serving as his/her own control. Core body temperature was measured using 3 different devices: (1) a fiberoptic MRI-compatible skin surface temperature probe (MRI-skin) located on the childs skin surface; (2) a fiberoptic MRI-compatible temperature probe modified with a single-use sleeve at the tip (MRI-core), located in the nasopharynx; and (3) a standard temperature monitor (STRD) located in the esophagus or nasopharynx. The Bland–Altman method was used for statistical analysis. RESULTS: We enrolled 60 children aged 7.8 ± 6 years (mean ± SD) weighing 32.4 (±26.4) kg. The estimated difference between the STRD and MRI-core measurements of core temperature was 0.06°C (confidence interval [CI]: −0.02, 0.15), and between the STRD and the MRI-skin 1.19°C (CI: 0.97, 1.41). According to the Bland–Altman analysis, the 95% limits of agreement ranged from −0.9 to 3.4 and from −1.3 to 1.2 between the STRD and the MRI-skin probe and the MRI-core probe, respectively. DISCUSSION: Our results show good agreement between standard esophageal measurements of core temperature and core temperature measured using a modified MRI-core probe during general anesthesia in a general surgical pediatric population. The ability to accurately assess core temperature in the MRI suite may safely allow longer scan times and therefore reduce repeat anesthetic exposure, improve patient safety, and enhance the quality of care in children.

Extent of right hepatectomy determines postoperative donor albumin and bilirubin changes: new insights.

Background: Changes in donor plasma albumin (Alb) and bilirubin (Tbili) are common following right hepatectomy for liver transplantation. We conducted a retrospective study to determine whether the size of the liver resection and the estimated blood loss (EBL) impact these laboratory values in the first week (early) and third week (late) postoperatively.

Noninfectious Fever in the Near-Term Pregnant Rat Induces Fetal Brain Inflammation: A Model for the Consequences of Epidural-Associated Maternal Fever.

BACKGROUND: Women laboring with epidural analgesia experience fever much more frequently than do women who chose other forms of analgesia, and maternal intrapartum fever is associated with numerous adverse consequences, including brain injury in the fetus. We developed a model of noninfectious inflammatory fever in the near-term pregnant rat to simulate the pathophysiology of epidural-associated fever and hypothesized that it would produce fetal brain inflammation. METHODS: Twenty-four pregnant Sprague-Dawley rats were studied at 20 days gestation (term: 22 days). Dams were treated by injection of rat recombinant interleukin (IL)-6 or vehicle at 90-minute intervals, and temperature was monitored every 30 minutes. Eight hours after the first treatment, dams were delivered of fetuses and then killed. Maternal IL-6 was measured at delivery. Fetal brains (n = 24) were processed and stained for ED-1/CD68, a marker for activated microglia, and cell counts in the lateral septal and hippocampal brain regions were measured. Fetal brains were also stained for cyclooxygenase-2 (COX-2), a downstream marker of neuroinflammation. Eight fetal brains were further analyzed for quantitative forebrain COX-2 by Western blotting compared to a &bgr;-actin standard. Maternal temperature and IL-6 levels were compared between treatments, as were cell counts, COX-2 staining, and COX-2 levels by Mann-Whitney U test, repeated-measures analysis of variance, or Fisher exact test, as appropriate. RESULTS: Injection of rat IL-6 at 90-minute intervals produced an elevation of maternal temperature compared to vehicle (P < .0001). IL-6 levels were elevated to clinically relevant levels at delivery in IL-6 compared to vehicle-treated animals (mean ± standard deviation: 923 ± 97 vs 143 ± 94 pg/mL, P = .0006). ED-1–stained cells were present in significantly higher numbers in fetal brains from IL-6 compared to saline-treated dams (median [interquartile range]: caudal hippocampus, 99 [94–104] and 64 [57–68], respectively, P = .002; lateral septum, 102 [96–111] and 68 [65–69], respectively, P = .002), as well as COX-2 immunostaining (lateral septum, 22 [20–26] and 17 [15–18], respectively, P = .005; dorsal hippocampus, 27 [22–32] and 16 [14–19], respectively, P = .013) and quantitative COX-2 Western blotting activity (mean ± standard error of the mean: vehicle, 0% of &bgr;-actin intensity versus IL-6, 41.5% ± 24%, P < .001). CONCLUSIONS: Noninfectious inflammatory fever is inducible in the near-term pregnant rat by injection of IL-6 at levels comparable to those observed during human epidural labor analgesia. Maternal IL-6 injection causes neuroinflammation in the fetus.