Predictive performance of the Domino, Hijazi, and Clements models during low-dose target-controlled ketamine infusions in healthy volunteers.

BACKGROUND: Healthy volunteers received low-dose target-controlled infusions (TCI) of ketamine controlled by the Domino model while cognitive function tests and functional neuroimaging were performed. The aim of the current study was to assess the predictive performance of the Domino model during these studies, and compare it with that of three other ketamine models. METHODS: Fifty-eight volunteers received ketamine administered by a TCI device on one or more occasions at target concentrations of either 50, 100, or 200 ng ml-1. At each target concentration, two or three venous blood samples were withdrawn during infusion, with a further sample after the infusion ended. Ketamine assays were performed by gas chromatography. The plasma concentration time courses predicted by the Hijazi, Clements 125, and Clements 250 models were calculated retrospectively, and the predictive performance of each of the models was assessed using Varvel methodology. RESULTS: For the Domino model, bias, inaccuracy, wobble, and divergence were - 2.7%, 33.9%, 24.2%, and 0.1463% h-1, respectively. There was a systematic increase in performance error over time. The Clements 250 model performed best by all criteria, whereas the Hijazi model performed least well by all criteria except for bias. CONCLUSIONS: Performance of the Domino model during control of low-dose ketamine infusions was sub-optimal. The Clements 250 model may be a better model for controlling low-dose TCI ketamine administration.

Ketamine disrupts frontal and hippocampal contribution to encoding and retrieval of episodic memory: an fMRI study.

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine produces episodic memory deficits. We used functional magnetic resonance imaging to characterize the effects of ketamine on frontal and hippocampal responses to memory encoding and retrieval in healthy volunteers using a double-blind, placebo-controlled, randomized, within-subjects comparison of two doses of intravenous ketamine. Dissociation of the effects of ketamine on encoding and retrieval processes was achieved using two study-test cycles: in the first, items were encoded prior to drug infusion and retrieval tested, during scanning, on drug; in the second, encoding was scanned on drug, and retrieval tested once ketamine plasma levels had declined. We additionally determined the interaction of ketamine with the depth of processing that occurred at encoding. A number of effects upon task-dependent activations were seen. Overall, our results suggest that left frontal activation is augmented by ketamine when elaborative semantic processing is required at encoding. In addition, successful encoding on ketamine is supplemented by additional non-verbal processing that is incidental to task demands. The effects of ketamine at retrieval are consistent with impaired access to accompanying contextual features of studied items. Our findings show that, even when overt behaviour is unimpaired, ketamine has an impact upon the recruitment of key regions in episodic memory task performance.

Acute ketamine administration alters the brain responses to executive demands in a verbal working memory task: an FMRI study.

We have used functional MRI to determine the effects of ketamine on brain systems activated in association with a working memory task. Healthy volunteers received intravenous infusions of placebo, ketamine at 50 ng/ml plasma concentration, and ketamine at 100 ng/ml. They were scanned while carrying out a verbal working memory task in which we varied the executive requirements (manipulation vs maintenance processes) and the mnemonic load (three vs five presented letters). We previously showed that ketamine produces a specific behavioral impairment in the manipulation task. In the current study, we modified tasks in order to match performance across drug and placebo conditions, and used an event-related fMRI design, allowing us to remove unsuccessful trials from the analysis. Our results suggest a task-specific effect of ketamine on working memory in a brain system comprising frontal cortex, parietal cortex, and putamen. When subjects are required to manipulate presented letters into alphabetical order, as opposed to maintaining them in the order in which they were presented, ketamine is associated with significantly greater activity in this system, even under these performance-matched conditions. No significant effect of ketamine was seen in association with increasing load. This suggests that our findings are not explicable in terms of a nonspecific effect of ketamine when task difficulty is increased. Rather, our findings provide evidence that the predominant effects of low, subdissociative doses of ketamine are upon the control processes engaged by the manipulation task. Furthermore, we have shown that ketamine's effects may be elucidated by fMRI even when overt behavioral measures show no evidence of impairment.

The 2002 Lindberg Award. PRN vs regularly scheduled opioid analgesics in pediatric burn patients.

Very little has been published on treating acute pain in children younger than the age of 3 for burns or any other trauma etiology. This study prospectively monitored the pain behavior and opioid analgesic intake of 31 pediatric burn patients (mean age = 23.71 months; SD = 15.75). Twelve of those children were randomized to conditions in which they either received opioid analgesics pro re nata (ie, as needed, pain contingent) or on a regular basis. The two groups did not show differences in demonstrable pain but, interestingly, they received equivalent does of opioid analgesics. As such, the pro re nata group was likely medicated largely on a regularly scheduled basis. For most of the remaining (nonrandomized) subjects, physicians ordered regularly scheduled opioid analgesics, suggesting that this practice has become largely institutionalized in the study setting. Information on pediatric opioid analgesic dosing and pain measurement strategies for nonverbal subjects can be derived from the findings.

A comparison of oral transmucosal fentanyl citrate and oral oxycodone for pediatric outpatient wound care.

Analgesia for pediatric burn wound care in the outpatient clinic is constrained by time, personnel, and/or monitoring capabilities, yet may improve patient satisfaction and comfort, clinic efficiency, and patient throughput. The ideal analgesic in this increasingly common setting should be palatable, provide potent, rapid, and brief analgesia, and require minimal appropriate monitoring. Using a placebo-controlled, double-blind design we compared oral transmucosal fentanyl citrate (OTFC, approximately 10 microg/kg) and oral oxycodone (0.2 mg/kg) in 22 pediatric outpatient wound care procedures (ages 5-14 years). Pulse oximetry, vital signs, side effects, patient pain scores, and observer scores for cooperation, anxiety, and sedation were recorded. OTFC and oral oxycodone resulted in similar outcome measures and vital signs, and no significant side effects. The taste of OTFC was preferred. We conclude that OTFC and oral oxycodone are safe and effective analgesics in the setting of monitored outpatient wound care in children, and that OTFC offers the advantage of improved palatability.

Effectiveness of virtual reality-based pain control with multiple treatments.

OBJECTIVE: The current study explored whether immersive virtual reality continues to reduce pain (via distraction) with repeated use. SETTING: The study was conducted in a burn care unit at a regional trauma center. PATIENTS: Seven patients aged 9-32 years (mean age of 21.9 years; average of 23.7% total body surface area burned [range, 3-60%]) performed range-of-motion exercises of their injured extremity under an occupational therapist's direction on at least 3 separate days each. INTERVENTION: For each physical therapy session, each patient spent equal amounts of time in virtual reality and in the control condition (no distraction). The mean duration of physical therapy in virtual reality was 3.5, 4.9, and 6.4 minutes for the first, second, and third session, respectively. Condition order was randomized and counter-balanced. OUTCOME MEASURES: For each of the three physical therapy sessions, five visual analog pain scores for each treatment condition served as the dependent variables. RESULTS: Pain ratings were statistically lower when patients were in virtual reality, and the magnitude of pain reduction did not diminish with repeated use of virtual reality. The results of this study may be examined in more detail at www.vrpain.com. CONCLUSIONS: Although the small sample size limits generalizability. results provide converging preliminary evidence that virtual reality can function as a strong nonpharmacological pain reduction technique for burn patients during physical therapy. Results suggest that virtual reality does not diminish in analgesic effectiveness with three (and possibly more) uses. Virtual reality may also have analgesic potential for other painful procedures or pain populations. Practical implications are discussed.

The Unna "cap" as a scalp donor site dressing.

Deep scalp donor sites can be difficult to manage because of the higher incidence of healing complications that can make daily wound care exquisitely painful. When faced with this problem, we prospectively studied the Unna "cap" dressing on the scalp. Group 1 received our standard treatment--Xeroform gauze (Sherwood Medical, St Louis, Mo) and daily wound care. Group 2 received the Unna cap--Aquaphor gauze (Beiersdorf, Norwalk, Conn) and Dome Paste gauze (Bayer Corp, West Haven, Conn) with wound care every 3 days. Pain, healing time, and costs were compared. Twelve patients between the age of 1 and 54 years were studied. A significant number of patients in Group 1 developed wound complications after initial healing, resulting in a longer length of stay and higher costs. Group 2 reported significantly less procedural pain, comparable healing (11 days +/- 2 SD), and fewer dressing changes, resulting in an institutional savings of $5.51 to $16.25 per patient up to postoperative day 13. This study supports use of the Unna cap as a less painful, safe, and cost-effective alternative to our standard deep scalp donor site dressing.

P-selectin blockade following fluid-percussion injury: behavioral and immunochemical sequelae.

Traumatic brain injury (TBI) can cause polymorphonuclear leukocyte (PMN) migration into brain parenchyma, mediating various cytodestructive mechanisms. We examined the effect of blocking leukocyte/endothelial cell adhesion molecules (CAMs) on the anatomic and behavioral sequelae in lateral fluid-percussion injury in rats. Monoclonal antibodies (MAb) directed against a functional (PB1.3) or nonfunctional (PNB1.6) epitope on endothelial P-selectin were used as treatments. Subjects were tested in the Morris water maze (MWM) at 7 and 14 days postinjury then immunohistochemistry was performed using antibodies that recognize ChAT, GFAP and OX-42. A second set of animals underwent myeloperoxidase (MPO) assay in the brain parenchyma and a third set was used to examine neutrophil migration using the MAb RP-3. Time in quadrant, but not escape latency or proximity improved with PB1.3 (p < 0.05). Similarly, PB1.3 reduced MPO levels after injury (p < 0.05), in the ipsilateral cortex. No significant difference occurred in neutrophil counts in cortex, corpus callosum, hippocampus, and thalamus between injured only rats and injured rats treated with PB1.3. Quantitative analysis of cholinergic cells in the medial septum showed a protective effect by PB1.3. Densitometry readings of GFAP and OX-42 immunolabeling revealed no discernible differences between the treated and untreated injured rats. Qualitatively, there was no difference in microglia or astrocyte response to treatment. Treatment with P-selectin blockade in brain-injured rats may reduce PMN migration into brain, help preserve cholinergic immunolabeling of medial septal nucleus neurons, and may alleviate mnemonic deficits.

A comparison of oral transmucosal fentanyl citrate and oral hydromorphone for inpatient pediatric burn wound care analgesia.

The ideal oral wound care analgesic for children should be palatable, provide potent analgesia of rapid onset and short duration, and require minimal, yet appropriate, monitoring. With use of a double-blinded crossover design, we compared the efficacy and safety of oral transmucosal fentanyl citrate (OTFC) (approximately 10 micrograms/kg) with the efficacy and safety of oral hydromorphone (60 micrograms/kg) in 14 pediatric inpatients (ages 4 to 17 years) undergoing daily burn wound care in a ward setting. Pulse oximetry, vital signs, side effects, patient pain scores, and observer scores for cooperation, anxiety, and sedation were recorded. Pulse oximetry, vital signs, cooperation, sedation, incidence of nausea or vomiting, and the amount of time it took to resume normal activities were similar in both treatment groups. OTFC resulted in improved pain scores before wound care and improved anxiolysis during wound care, but at other points it was similar in effect to hydromorphone. We conclude that OTFC is a safe and effective analgesic, that it may provide minor improvements in analgesia and anxiolysis compared with hydromorphone, and that it offers a palatable alternative route of opioid administration without intravenous access for wound care procedures in children.

The role of leukocyte emigration and IL-8 on the development of lipopolysaccharide-induced lung injury in rabbits.

Leukocyte emigration and alveolar macrophage-derived cytokines may contribute to lung microvascular injury associated with adult respiratory distress syndrome. We have used mAbs against cell adhesion molecules on leukocytes (anti-CD18 and anti-CD49d) or against IL-8 to investigate these contributions. Intratracheal (i.t.) instillation of LPS (50 microg/kg) caused a significant increase in bronchoalveolar lavage polymorphonuclear leukocytes (PMNs) without an increase in mononuclear cells (MNCs) or an increase in lung permeability. Injection of LPS (10 microg/kg) i.v. at 24 h after i.t. LPS caused significant increases in bronchoalveolar lavage PMNs, MNCs, IL-8, and monocyte chemotactic protein-1, as well as increases in lung permeability. Rabbits that were administered i.t. LPS followed by i.v. LPS and treated with anti-CD18 mAb had a significantly lower lung permeability index and emigration of fewer PMNs but no change in MNC emigration compared with saline treatment. Anti-IL-8 mAb treatment resulted in a significantly lower lung permeability index with no change in PMN emigration compared with no treatment. These results suggest that PMN emigration is necessary but not sufficient for the development of LPS-induced lung injury, and that IL-8 plays a significant role in PMN-dependent lung injury, independent of PMN emigration.

Antibiotic therapy determines subcutaneous Escherichia coli abscess formation after CD18 inhibition in rabbits.

Monoclonal antibodies (MAbs) that interrupt polymorphonuclear neutrophil (PMN)-endothelial cell adhesion can ameliorate PMN-mediated injury, including burn-induced inflammatory injury, but can also impair PMN-mediated defense against bacterial infection. We report the effects of combined anti-adhesion and antibiotic therapy on local infectious sequelae after subcutaneous Escherichia coli inoculation in rabbits treated with anti-CD18 (60.3) or anti-P-selectin (PB1.3) MAb. Ampicillin or ceftriaxone were administered for 72 hours. PMN emigration was assessed at 24 hours and local infectious sequelae at 7 days. In ampicillin/60.3-treated rabbits, E. coli inoculation resulted in impaired PMN emigration and increased infectious complications, with abscesses forming at a 10,000-fold lower inoculation concentration compared with other MAb-antibiotic treatment groups. We conclude that (1) CD18, but not P-selectin blockade interferes with PMN emigration and host defense to subcutaneous E. coli, and (2) appropriate antibiotic therapy can prevent the local infectious events caused by CD18 inhibition.

Opiate-induced respiratory depression in young pediatric burn patients.

Three children younger than 5 with minor burns (< 5% total body surface area) experienced opiate-induced respiratory depression early in hospitalization. This prompted a decrease in the recommended opiate analgesic-dose ranges on our pediatric worksheet. In reviewing 57 admissions, 31 pre- and 26 post-dose change, the amount of opioid equivalents/kg received on admission day did not differ significantly. However, the incidence of respiratory depressive events decreased. Lower opiate-dose guidelines might improve the safe administration of these medications to young children. Other factors- such as concomitant sedative medications, previously administered opiate analgesics, and underlying medical conditions-also must be considered when giving initial doses of opiate analgesics in the burn center.

Lorazepam as an adjunct to opioid analgesics in the treatment of burn pain.

Benzodiazepines are commonly used to supplement opioid analgesics in treating procedural pain during the treatment of major burn injuries. To date, no study has investigated whether benzodiazepines actually have an analgesic or anxiolytic effect in such circumstances. Seventy-nine patients admitted to a major regional burn center were randomly assigned to groups that received 1 mg of lorazepam or a placebo in addition to their standard opioid analgesics. A strong analgesic effect of lorazepam was not observed when treatment groups were compared independent of their baseline pain ratings. However when patients who had high baseline pain were compared, lorazepam resulted in a significant reduction in pain ratings (adjusted post-treatment VAS mean score = 54.28; adjusted control VAS mean score = 69.06). Trait anxiety did not predict those patients who had an analgesic effect with lorazepam, but state anxiety did prove to be a covariate with visual analogue score decreases in pain reports.

Binding of human peripheral blood polymorphonuclear leukocytes to E-selectin (CD62E) does not promote their activation.

E-selectin (CD62E) is a cytokine-inducible endothelial cell adhesion molecule that tethers polymorphonuclear leukocytes (PMNs) and supports PMN rolling under conditions of flow. We examined whether interaction of PMNs with E-selectin also leads to activation of CD11b/CD18 (Mac-1, alphaMbeta2), an event that can promote firm adhesion. PMNs were added to monolayers of IL-1beta-activated HUVECs and Chinese hamster ovary (CHO) cells transfected with E-selectin cDNA. PMN activation was assessed by 1) increased CD11b/CD18 surface expression, 2) appearance of activation epitope on CD11b/CD18 (CD11b*) detected by mAb CBRM1/5, and 3) decreased L-selectin (CD62L) expression, as determined by flow cytometry. Both adherent and nonadherent supernatant PMNs became activated on IL-1beta-pretreated HUVECs. This activation was not affected by CD62E-blocking mAb P6E2. The activation state of PMNs adhered to CHO cells transfected with E-selectin cDNA was not increased over background and was similar to that of PMNs exposed to parent CHO cells. The findings were confirmed using confocal microscopy, which allowed staining of the cells for CD11b* in situ. In concert, the results suggest that PMN binding to E-selectin does not elicit inter-receptor signaling that could result in strengthening of PMN adhesion to endothelium.

CD18 adhesion blockade decreases bacterial clearance and neutrophil recruitment after intrapulmonary E. coli, but not after S. aureus.

Leukocyte emigration in the lung occurs by both CD18-dependent and -independent mechanisms that are stimulus specific. We examined the effect of CD18 blockade (mAb 60.3) on neutrophil (PMN) emigration into, and bacterial clearance from, the lung. After intravenous treatment with either mAb 60.3 or saline, rabbits were given an intralobar inoculation with 10(9) colony-forming units of either Staphylococcus aureus or Escherichia coli. Four hours after inoculation, lungs were lavaged to assess PMN emigration. CD18 blockade reduced PMN emigration to E. coli by 76% but only 45% to S. aureus. Experiments to determine bacterial recovery from the lungs at 4, 8, and 24 h after inoculation showed that CD18 blockade impaired the early (4 h) clearance of E. coli but not S. aureus. These findings suggest that PMN emigration to intrapulmonary S. aureus is largely CD18-independent. In contrast, intrapulmonary E. coli elicits CD18-mediated PMN emigration. CD18 blockade results in impaired clearance of E. coli but not S. aureus from the lung.

Neutrophil adhesion molecule expression is comparable in perinatal rabbits and humans.

BACKGROUND: Human newborns, particularly those born before full term, are more susceptible to bacterial infections as a result of impaired host defense mechanisms. Compared with adults, circulating leukocytes from human newborns (preterm and full-term gestations) and newborn rabbits (full-term gestation) have low resting levels of CD62L (L-selectin) and do not significantly increase surface expression of CD18 after inflammatory stimulation. To determine the potential utility of preterm rabbits in investigations of perinatal human conditions, the authors compared the surface expression of the beta 2-integrin CD18 and CD62L (L-selectin) on polymorphonuclear leukocytes (PMNs) from perinatal rabbits and perinatal humans, both under resting conditions and after in vitro activation with inflammatory stimulants. METHODS: After erythrocyte lysis of whole-blood samples, leukocytes from 7-day-old, full-term (31-day gestation), and preterm (24-day gestation) rabbits, as well as full-term (37-42 week gestation) and preterm (27-36 week gestation) human newborns were prepared and stimulated in vitro at 37 degrees C with either C5a or phorbol myristate acetate. After fluorescence labeling of CD18 and CD62L with monoclonal antibodies, PMN adhesion molecule expression was assessed by flow cytometry. RESULTS: Constitutive CD18 expression was not significantly different between perinatal and adult humans but was reduced in all perinatal rabbits compared with adults. Inflammatory stimulation caused significant increases in CD18 expression in adult human PMNs but not in full-term and preterm newborns. Changes in CD18 expression in adult and preterm rabbits after stimulation, although in the same direction as humans, were more variable. In both species, constitutive CD62L expression on PMNs from all perinates was significantly lower than in adults. However, CD62L was shed to similar degrees after inflammatory stimulation in all groups. CONCLUSIONS: Preterm rabbits may provide a potentially useful experimental model to study PMN adhesion and host defense in the perinatal period, particularly preterm gestations. Specific advantages and limitations of rabbits in such studies are discussed.

Blocking L-selectin function attenuates reperfusion injury following hemorrhagic shock in rabbits.

Leukocyte adhesion molecule (LAM) blockade reduces ischemia-reperfusion injury. We tested the hypothesis that a monoclonal antibody (MAb) that recognizes a functional epitope of L-selectin would decrease hemorrhagic shock-induced reperfusion injury. Anesthetized rabbits were subjected to 2 h of hemorrhagic shock (cardiac output reduced to 30% of baseline), then given one of the following treatments: MAbs that recognize functional domains of L-selectin (LAM1-3), CD18 (60.3), MAbs that recognize a nonfunctional domain on L-selectin (LAM1-14), or saline, immediately before resuscitation with shed blood. Additional fluids were administered as needed to maintain cardiac output at baseline levels for 6 h. The cumulative fluid resuscitation after MAb LAM1-3 (58 +/- 34 ml/kg) was not significantly different from after MAb 60.3 (21 +/- 24 ml/kg) or MAb LAM1-14 (66 +/- 51 ml/kg), but it was significantly less than saline-treated controls (142 +/- 142 ml/kg). However, two animals treated with MAb LAM1-14 died before 6 h. If their resuscitation volumes are projected to 6 h by linear regression, then the LAM1-14-treated group required significantly greater volume (101 +/- 99 ml/kg) than the MAb LAM1-3-treated group. We conclude that MAbs to a functional domain on L-selectin are protective against reperfusion-injury following hemorrhagic shock.

L-selectin (CD62L) blockade does not impair peritoneal neutrophil emigration or subcutaneous host defense to bacteria in rabbits.

Neutrophil (PMN) recruitment into systemic inflammatory sites in vivo is thought to be initiated by selectin-mediated endothelial adherence. We explored the role of L-selectin (CD62L) in leukocyte emigration following instillation of bacteria into the peritoneum or s.c. skin in rabbits. Pretreatment with blocking mAb against L-selectin (LAM1.3) reduced peritoneal PMN emigration 4 h after i.p. inoculation with 10(10) CFU of Escherichia coli by only 17% compared with animals receiving a nonblocking L-selectin mAb (LAM1.14). Peritoneal PMNs from saline-treated rabbits demonstrated a complete absence of L-selectin, whereas those from LAM1.3-treated animals retained 43% of their baseline L-selectin expression. This suggests that L-selectin shedding is not a requisite event for PMN emigration under these conditions. In rabbits given s.c. inoculations with either Staphylococcus aureus or E coli, pretreatment with mAb LAM1.3 did not significantly impair PMN emigration at 24 h, nor increase the incidence, size, or associated mortality of resulting abscesses at 7 days compared with animals receiving nonblocking mAb LAM1.14. We conclude that: 1) mAb blockade of L-selectin in vivo only modestly affects acute, E. coli-induced peritoneal PMN emigration; and 2) L-selectin blockade does not increase infectious sequelae associated with s.c. bacterial inoculation. These findings of only mildly reduced PMN emigration into the peritoneum and no alteration in s.c. host defense differ from those reported with L-selectin blockade under other, nonbacterial inflammatory conditions, and suggest that redundant selectin-mediated mechanisms (P- and E-selectin) are sufficient for normal PMN emigration in response to bacterial stimulation.

CD18-independent mechanism of neutrophil emigration in the rabbit lung after ischemia-reperfusion.

BACKGROUND: Reperfusion of ischemic lung causes an inflammatory pulmonary vascular injury characterized by increased vascular permeability and migration of inflammatory cells into the alveoli. Migration of neutrophils into the alveolus during reperfusion after 24 hours of unilateral pulmonary artery occlusion has been shown to be in part dependent on the CD18 adhesion molecule on the cell surface. The current study investigated whether reperfusion lung injury after a 1-hour period of complete lung ischemia was CD18 dependent. METHODS: Eighteen rabbits were assigned to one of three groups. Groups 1 and 2 were subjected to one hour of in situ right hilar occlusion followed by 2 hours of reperfusion. Group 3 was subjected to identical surgical dissection but the right hilum was never occluded. Group 1 rabbits received saline solution (1 mL/kg) before hilar occlusion and group 2 rabbits, monoclonal antibody 60.3, a blocking antibody for the CD18 adhesion molecule on the neutrophil surface (2 mg/kg). In 3 of the antibody-treated rabbits, flow cytometry was performed on blood neutrophils before and after administration of the antibody and 120 minutes after reperfusion. RESULTS: The rabbits in groups 1 and 2 had significantly increased alveolar neutrophil infiltrate and increased pulmonary vascular resistance compared with the rabbits in group 3. However, there was no significant difference between group 1 (saline solution treated) and group 2 (antibody treated). Antibody treatment did not block migration of neutrophils into the alveoli. Flow cytometry of circulating neutrophils demonstrated that CD18 was upregulated after reperfusion and that CD18 was fully blocked after antibody treatment for the duration of the study. CONCLUSIONS: We conclude that a 1-hour period of warm ischemia followed by reperfusion results in upregulation of CD18 but that emigration of the neutrophils into the alveoli is not CD18 dependent in this injury.