Pharmacokinetics of morphine and its glucuronidated metabolites in burn injuries.

OBJECTIVE: To investigate the effects of major thermal burn injury and continuous intravenous morphine infusion on the disposition of morphine and its glucuronidated metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) once a week for three weeks. CASE SUMMARIES: Five patients with major first-, second-, or third-degree burn injuries received long-term intravenous morphine infusion. The required dose varied greatly (from 4 to 39.5 mg/h). The steady-state concentrations of morphine, M3G, and M6G ranged from 20 to 452, 29 to 3436, and 20 to 1240 mumol/L, respectively. The systemic clearance (Cls) of morphine ranged from 14.8 to 40.3 mL/min/kg and did not change over time. The ratios of M6G and M3G to morphine were not affected by dose, even with the wide variation of intravenous dosage. Morphine kinetics appeared to be first-order. Mean recovery of morphine, M3G, and M6G in urine was 1.7 +/- 1.0%, 42.0 +/- 16.8%, and 11.8 +/- 3.2%, respectively, and renal clearance ranged from 8 to 64, 26 to 325, and 59 to 589 mL/min, respectively. Mean pain intensity ratings at rest remained low and stable (0.7 +/- 0.9 on day 7, 0.4 +/- 0.3 on day 14, 0 +/- 0 on day 21). DISCUSSION: To our knowledge, this is the first published report describing morphine, M3G, and M6G disposition in patients with major thermal burn injury. The Cls of morphine is similar to that observed in other patient populations and healthy subjects, suggesting that the presence of major burn injuries or a continuous morphine infusion over a three-week period may not contribute significantly to the variability among individuals. In these cases, the renal clearance of morphine and its glucuronides was within the range of values reported for other populations of patients and healthy subjects. Recovery of morphine and its glucuronides in urine was also similar to that in healthy individuals. CONCLUSIONS: These cases suggest that the effects of major burn injuries and of long-term intravenous infusion of morphine did not seem to modify morphine, M3G, and M6G disposition. Among patients with burn injuries, the severity of burns of duration of administration are not a cause of nonlinear kinetic of morphine or of morphine resistance. The morphine infusion rate was substantially variable and not directly related to its clearance, suggesting that monitoring of morphine should be focused on the clinical response.     

Revealing tacit knowledge used by experienced health professionals for interprofessional collaboration

ABSTRACT

With the current interest in interprofessional collaboration in health care as a response to ever-increasing complexity of health issues and scarcity of resources, many higher education institutions are developing interprofessional education (IPE) programs. However, there has been little empirical work on what. With the current interest for interprofessional collaboration in health care ever-increasing knowledge and skills are required to work collaboratively between health professions. We have undertaken to describe interprofessional collaboration as a practice largely underpinned by tacit knowledge acquired by experienced clinicians. Clinicians from all health professions in a large francophone university in Eastern Canada were invited to participate in explicitation interviews. Explicitation interviews require participants to freely recall an interprofessional collaboration event (e.g., team meeting or joint care delivery) and describe specific actions they personally enacted. An experienced health professional encounters many interprofessional situations over time; the actions they describe reflect their personal theories about the practice. Hence, it is highly probable that they use them frequently when working with colleagues in clinical settings. Unveiled tacit knowledge was divided into four themes: the importance of a sense of belonging to a team, the imperative to meet face-to-face, the practice of soliciting the working hypotheses of colleagues, and the art of summarizing meeting discussions.     

Immunobiology of allogeneic peripheral blood mononuclear cells mobilized with granulocyte-colony stimulating factor

The use of mobilized peripheral blood (PB) stem cells for autologous transplantation initially generated much enthusiasm because of enhanced engraftment in comparison to marrow stem cells and avoidance of general anesthesia for the donor. Its application to the allogeneic setting seemed inevitable. For obvious ethical reasons, allogeneic donors are mobilized with cytokines only, mainly granulocyte colony-stimulating factor (G-CSF). Results from preliminary studies suggest that in comparison to standard bone marrow transplants, outcomes such as engraftment, host-versus-graft reaction, graft-versus-host disease, graft-versus-leukemia and immunological reconstitution may be different. Surprisingly, G-CSF, previously recognized as a late acting lineage-specific factor for neutrophil production, not only disrupts homeostasis between stem cells and their microenvironment, but also induces significant quantitative and qualitative changes in the accessory cell compartment, affecting lymphocytes, monocytes, natural killer, dendritic, and stromal cells. Furthermore, mobilization of huge numbers of non-professional antigen presenting cells (CD34+ stem cells) amplifies the tolerizing potential of PB stem cell grafts. Thus, G-CSF mobilization provides PB transplants with different immunobiologic properties in comparison to standard bone marrow grafts. Whether these immunobiologic differences will lead to better transplant outcomes remains to be shown through much awaited results of large randomized clinical trials.     

Pontine reticulospinal projections in the neonatal mouse: Internal organization and axon trajectories

We recently characterized physiologically a pontine reticulospinal (pRS) projection in the neonatal mouse that mediates synaptic effects on spinal motoneurons via parallel uncrossed and crossed pathways (Sivertsen et al. [2014] J Neurophysiol 112:1628–1643). Here we characterize the origins, anatomical organization, and supraspinal axon trajectories of these pathways via retrograde tracing from the high cervical spinal cord. The two pathways derive from segregated populations of ipsilaterally and contralaterally projecting pRS neurons with characteristic locations within the pontine reticular formation (PRF). We obtained estimates of relative neuron numbers by counting from sections, digitally generated neuron position maps, and 3D reconstructions. Ipsilateral pRS neurons outnumber contralateral pRS neurons by threefold and are distributed about equally in rostral and caudal regions of the PRF, whereas contralateral pRS neurons are concentrated in the rostral PRF. Ipsilateral pRS neuron somata are on average larger than contralateral. No pRS neurons are positive in transgenic mice that report the expression of GAD, suggesting that they are predominantly excitatory. Putative GABAergic interneurons are interspersed among the pRS neurons, however. Ipsilateral and contralateral pRS axons have distinctly different trajectories within the brainstem. Their initial spinal funicular trajectories also differ, with ipsilateral and contralateral pRS axons more highly concentrated medially and laterally, respectively. The larger size and greater number of ipsilateral vs. contralateral pRS neurons is compatible with our previous finding that the uncrossed projection transmits more reliably to spinal motoneurons. The information about supraspinal and initial spinal pRS axon trajectories should facilitate future physiological assessment of synaptic connections between pRS neurons and spinal neurons. J. Comp. Neurol. 524:1270–1291, 2016. © 2015 Wiley Periodicals, Inc.     

Comparison of direct health care costs related to the pharmacological treatment of osteoporosis and to the management of osteoporotic fractures among compliant and noncompliant users of alendronate and risedronate: a population-based study

Summary  This population-based study aimed to compare direct health care costs related to the pharmacological treatment of osteoporosis and to the management of osteoporotic fractures among compliant and noncompliant users of alendronate and risedronate. During a 2-year follow-up period, compared to those with medication possession ratio (MPR) ≥ 80%, women with MPR < 80% incurred significantly higher physician care costs and hospital care costs. Introduction  This study aimed to compare direct health care costs related to the treatment of osteoporosis and osteoporotic fractures among compliant and noncompliant users of alendronate and risedronate. Methods  A cohort of 15,027 women having initiated alendronate or risedronate was identified. MPR and direct health care costs (physician care, hospital care, drugs) were assessed during a 2-year period. Regression models were used to estimate mean predicted cost for compliant (MPR ≥ 80%) and noncompliant (MPR < 80%) women. Results  Mean predicted physician care cost (in Canadian dollars) was $51 among women with MPR < 80% and $34 among those with MPR ≥ 80%: mean difference $17, 95% confidence interval (CI) $2–22. Mean predicted hospital care cost was $568 among women with MPR < 80% and $379 among those with MPR ≥ 80%: mean difference $189, 95% CI $56–320. Mean predicted drug cost was $439 among women with MPR < 80% and $1,068 among those with MPR ≥ 80%: mean difference $−639, 95% CI $−649 to −629. Conclusion  Compared to compliant women, noncompliant women incurred significantly higher physician care and hospital care costs. Due to lower drug costs, total direct health care costs were lower among noncompliant women.    This study was funded by a grant from the Canadian Institutes of Health Research (Ottawa, Canada)     

Validity of CoaguChek S for home monitoring of anticoagulant therapy in pediatrics

BACKGROUND: CoaguChek S (Roche Diagnostics, Canada) is a portable device designed to monitor international normalized ratio (INR) by capillary puncture. Although the device is used in pediatrics, no study has evaluated its validity in patients of this population. OBJECTIVE: To evaluate the validity of CoaguChek S as an in-home INR monitor in patients younger than 18 years of age. METHODS: Data were based on 129 INR pairs collected from nine patients younger than 18 years of age followed up at an anticoagulation clinic between March 1, 2000, and January 19, 2004. The INRs from both the laboratory and CoaguChek S were used to evaluate concordance between the two methods using the intraclass correlation coefficient. RESULTS: The overall intraclass correlation coefficient between the CoaguChek S and the laboratory was 0.75 (95% CI 0.66 to 0.82). On average, CoaguChek S underestimated INRs by 0.11+/-0.54 units compared with those of the laboratory. INRs of 3.5 units and higher obtained with CoaguChek S were, on average, 0.49+/-1.09 units higher than those obtained in the laboratory. CONCLUSIONS: CoaguChek S appears to be a valid instrument for in-home INR monitoring for most patients younger than 18 years of age, with INR targets of 2.0 to 3.0 followed up by an anticoagulant therapy clinic's program. However, caution must be used when interpreting INRs higher than 3.5. Parents should perform a second test to confirm all CoaguChek S INR results higher than 4.0.     

Thiopental-induced neutropenia in two patients with severe head trauma

Thiopental has been used for decades in the treatment of refractory intracranial hypertension in patients with traumatic and nontraumatic head injuries. Commonly reported adverse effects include hypotension, hypokalemia, respiratory complications, and hepatic dysfunction. Neutropenia has rarely been reported as an adverse effect of thiopental. We witnessed probable thiopental-induced neutropenia in two patients with traumatic brain injuries who developed increased intracranial hypertension that was refractory to standard therapy. Based on a MEDLINE search of published case reports and literature, we propose two mechanisms by which thiopental-related neutropenia might be explained. The first is inhibition of inflammatory mediator nuclear factor-kappa B (NF-kappa B), leading to granulocyte apoptosis. The second mechanism involves inhibition of calcineurin. Although the precise link between these two mechanisms has not been elucidated, calcineurin is known to regulate NF-kappa B activity. Development of neutropenia does not appear to be correlated with time but may correlate with plasma concentrations of thiopental. The optimum management of drug-induced neutropenia is unclear. The decision to discontinue thiopental in patients who develop neutropenia should be made by weighing the risks versus benefits. Broad-spectrum antibiotics may be required in the presence of fever. The role of hematopoietic growth factors such as granulocyte colony-stimulating factor is not yet defined. Given the adverse infectious consequences of neutropenia, it is essential to closely monitor neutrophil counts in patients receiving thiopental.