Pharmacokinetics and effects of extravascularly administered dexmedetomidine : studies on pediatric and adult patients, and healthy adult volunteers

Patients undergoing surgery and other invasive procedures need sedation and pain relief. Many unpleasant sensations and experiences can be reduced by administration of conventional sedative and analgesic drugs, but most of these compounds are associated with troublesome adverse effects such as respiratory depression and nausea. Dexmedetomidine is a relatively new drug that acts by activating α2-adrenoceptors. It has received marketing authorisation for intensive care sedation and for procedural sedation of adult patients. In addition to its sedative property, dexmedetomidine exerts analgesic and antiemetic effects. In comparison to other analgesic and sedative agents, dexmedetomidine has minimal effects on respiration. Dexmedetomidine has been developed and approved for intravenous administration. Several reports exist on the use of intranasal and other extravascular routes of administration of dexmedetomidine. Nonetheless, the pharmacokinetic and pharmacodynamic properties of extravascularly administered dexmedetomidine have remained poorly characterized. The intranasal route of administration appears to be feasible for administration of dexmedetomidine to children, but there is rather little information available about the pharmacokinetics of dexmedetomidine in children. In the present series of studies, the pharmacokinetics and -dynamics of subcutaneously and intranasally administered dexmedetomidine were characterized in healthy volunteers and in pediatric patients. We also evaluated the anesthetic sparing effect of intranasally administered dexmedetomidine in pediatric patients undergoing ambulatory sedation, and the analgesic sparing effect of intranasally administered dexmedetomidine in adult patients undergoing hip arthroplasty under general anesthesia. The systemic bioavailability of subcutaneously administered dexmedetomidine was good (81%), but interindividual variation was large. After intranasal administration of dexmedetomidine in pediatric patients, on average the peak plasma concentrations were achieved in 37 minutes, with peak effects normally observed at 45 minutes. Peak concentrations and exposure to the study drug decreased with age. Intranasal doses of 2-3 μg/kg achieved clinically acceptable sedation in about 94% of pediatric patients undergoing magnetic resonance imaging. In adult patients undergoing total hip arthroplasty, the use of intranasal low-dose dexmedetomidine decreased postoperative opioid consumption in a clinically significant manner. Our findings provide support for the use of intranasal dexmedetomidine in pediatric patients requiring light or moderate sedation and in adult patients undergoing painful surgical procedures. Subcutaneous administration of dexmedetomidine appears promising e.g. for patients needing palliative sedation and analgesia, but further studies are warranted to confirm this proposal.Ekstravaskulaarisesti annostellun deksmedetomidiinin farmakokinetiikka ja vaikutukset : tutkimuksia aikuis- ja lapsipotilailla sekä terveillä vapaaehtoisilla aikuisilla Leikkauksiin ja muihin toimenpiteisiin tulevat potilaat tarvitsevat rauhoittavaa ja kipua lievittävää lääkitystä. Vaikka monia epämiellyttäviä oireita ja tuntemuksia voidaan lievittää tavanomaisilla kipu- ja rauhoittavilla lääkkeillä, liittyy niiden käyttöön usein hankalia haittavaikutuksia kuten hengityslamaa ja pahoinvointia. Deksmedetomidiini on uudehko aikuisten tehohoito- ja toimenpidepotilaiden rauhoittamiseen myyntiluvan saanut, α2-adrenoseptoreja aktivoiva lääkeaine, jolla on väsyttävä ja potilasta rauhoittava vaikutus, mutta lisäksi myös kipua ja pahoinvointia lieventäviä vaikutuksia. Deksmedetomidiinin etu verrattuna tavanomaisiin kipu- ja rauhoittaviin lääkkeisiin on sen hyvin vähäinen vaikutus potilaan hengitykseen. Deksmedetomidiini on kehitetty ja tarkoitettu annosteltavaksi laskimoon. Monia muitakin annostelureittejä, kuten annostelua nenän limakalvoille, on tutkittu. Deksmedetomidiinin annostelusta muuten kuin laskimon kautta on tehty kuitenkin vain vähän farmakokineettisiä ja farmakodynaamisia tutkimuksia. Vaikka annostelua nenän limakalvolle käytetäänkin jo lapsipotilailla varsin usein, ei sen imeytymistä ja käyttäytymistä elimistössä ole lapsipotilailla juurikaan tutkittu. Tässä tutkimussarjassa verrattiin ihon alle ja laskimoon annostellun deksmedetomidiinin farmakokinetiikkaa ja -dynamiikkaa terveillä vapaaehtoisilla aikuisilla sekä tutkittiin nenän limakalvoille annostellun deksmedetomidiinin farmakokinetiikkaa ja –dynamiikkaa lapsipotilailla. Tutkimme lisäksi nenän limakalvoille annostellun deksmedetomidiinin vaikutusta nukutuslääkkeen tarpeeseen sedaatiota tarvitsevilla lapsipotilailla sekä yleisanestesiassa tehdyn lonkkaproteesileikkauksen jälkeiseen kipulääkkeen tarpeeseen aikuispotilailla. Ihon alle annostellun deksmedetomidiinin hyötyosuus osoittautui hyväksi (81 %), mutta yksilöiden välinen vaihtelu oli suurta. Lapsipotilailla nenän limakalvoille annostellun deksmedetomidiinin huippupitoisuus plasmassa saavutettiin 37 min ja huippuvaikutus 45 min kuluttua lääkkeen annostelusta. Huippupitoisuus ja altistus lääkkeelle pienenivät iän myötä. Nenän limakalvoille annosteltu deksmedetomidiini aiheutti merkittävän sedaation annoksella 2-3 μg/kg. Aikuispotilailla nenän limakalvoille annosteltu pieniannoksinen deksmedetomidiini vähensi leikkauksen jälkeisen opioidikipulääkkeen tarvetta. Löydöksemme kannustavat käyttämään nenän limakalvoille annosteltua deksmedetomidiinia lapsipotilailla, jotka tarvitsevat kevyttä tai kohtalaista sedaatiota, sekä aikuispotilailla, joille tehdään kivuliaita leikkauksia. Myös ihon alle annosteltu deksmedetomidiini vaikuttaa lupaavalta esim. palliatiivista hoitoa saaville potilaille, mutta annostelusta tarvitaan lisää kliinisiä tutkimuksia

Continuous hemodialysis with citrate anticoagulation and standard dialysate for managing acute kidney injury in patients with moderate to severe hyponatremia-A retrospective study

Background: The safety of continuous veno-venous hemodialysis (CVVHD) with citrate-calcium anticoagulation for acute kidney injury (AKI) with coincident hyponatremia remains unclear. We aimed to explore the feasibility of CVVHD with standard dialysate and citrate-calcium anticoagulation in hyponatremic critically ill AKI patients.Methods: Thirty-seven of the 493 critically ill AKI patients requiring CVVHD and admitted to our intensive care unit during a 10-year period had hyponatremia (Results: Median plasma sodium concentration was 127 (IQR 124-129) mmol/L at CVVHD initiation. CVVHD duration was median 3 (IQR 1.5-5.5) days and the mean daily sodium load of the trisodium citrate solution during the first 3 days of CVVHD was 1754 (SD 730) mmol. The plasma sodium concentration increased a median 8 (IQR 5-10) mmol/L during the first 24 hours of CVVHD and excessively high plasma sodium correction (>8 mmol/L/24 h) was observed in 18 (48.6%) patients. However, increased mortality in association to rapid plasma sodium correction was not observed in this study.Conclusions: CVVHD using standard citrate-calcium anticoagulation effectively increased plasma sodium concentration in this study. However, excessively high plasma sodium correction was observed in half of the patients and the sodium load provided by the standard citrate anticoagulation solutions was substantial.</div

Mortality and associated risk factors in patients with blood culture positive sepsis and acute kidney injury requiring continuous renal replacement therapy-A retrospective study

ObjectivesSeptic acute kidney injury (AKI) requiring continuous renal replacement therapy (CRRT) carries a mortality risk nearing 50%. Risk factors associated with mortality in AKI patients undergoing CRRT with blood culture positive sepsis remain unclear as sepsis has been defined according to consensus criteria in previous studies.MethodsRisk factors associated with intensive care unit (ICU), 90-day and overall mortality were studied in a retrospective cohort of 126 patients with blood culture positive sepsis and coincident severe AKI requiring CRRT. Comprehensive laboratory and clinical data were gathered at ICU admission and CRRT initiation.Results38 different causative pathogens for sepsis and associated AKI were identified. ICU mortality was 30%, 90-day mortality 45% and one-year mortality 50%. Immunosuppression, history of heart failure, APACHE II and SAPS II scores, C-reactive protein and lactate at CRRT initiation were independently associated with mortality in multivariable Cox proportional hazards models. Blood lactate showed good predictive power for ICU mortality in receiver operating characteristic curve analyses with AUCs of 0.76 (95%CI 0.66-0.85) for lactate at ICU admission and 0.84 (95%CI 0.72-0.95) at CRRT initiation.ConclusionsOur study shows for the first time that lactate measured at CRRT initiation is predictive of ICU mortality and independently associated with overall mortality in patients with blood culture positive sepsis and AKI requiring CRRT. Microbial etiology for septic AKI requiring CRRT is diverse

Mortality and associated risk factors in perioperative acute kidney injury treated with continuous renal replacement therapy

Background: Perioperative acute kidney injury (AKI) is associated with multiple postoperative complications leading to prolonged hospital stay and higher costs. AKI requiring continuous renal replacement therapy (CRRT) after surgery has an incidence of 2-6% and mortality approximates 40-60%. Previous studies examining mortality in perioperative AKI patients managed with CRRT have concentrated on cardiac surgery patients and there are very limited data on broad surgical patient populations requiring CRRT. We examined long-term mortality and factors associated with poor outcome in a broad surgical population requiring CRRT for perioperative AKI during a 10-year period.Methods: Surgical patients admitted to the intensive care unit (ICU) of academic tertiary hospital requiring CRRT between years 2010-2019 were included. CRRT was performed using regional citrate-calcium-anticoagulation. Extracted data included patient demographics, comorbidities, and clinical parameters at ICU admission and at the initiation of CRRT. Creatinine and estimated glomerular filtration rate (eGFR) were measured at 1 year after ICU admission.Results: A total of 157 patients were included in the study. ICU mortality was 42.7%, 90-day mortality 58.0% and 1year mortality 62.4%. Blood lactate at ICU admission and CRRT initiation were independently associated with mortality in the multivariate models. Patients with lactate > 4 mmol/l had higher mortality than patients with normal lactate (77% vs. 21%) (p < 0.001). Creatinine (p = 0.004) and eGFR (p < 0.001) remained significantly altered at 1 year of follow-up compared to baseline.Conclusions: Patients undergoing surgery and requiring perioperative CRRT in the ICU have a high risk of mortality. Mortality appears to be independently associated with lactate levels

Feasibility of Intranasal Dexmedetomidine in Treatment of Postoperative Restlessness, Agitation, and Pain in Geriatric Orthopedic Patients

Objective The aim of this study was to report preliminary data on the use of intranasal dexmedetomidine to treat postoperative restlessness, agitation, and pain in 23 patients aged > 70 years and undergoing orthopedic surgery. Background Postoperative agitation and delirium are common among older adult patients undergoing orthopedic surgery. Most preparations used to treat agitation and delirium carry a risk for adverse events such as respiratory failure. Moreover, mere opioid therapy may be insufficient in treatment of pain. Dexmedetomidine, an alpha 2-adrenoreceptor agonist with sedative and analgesic properties, has been shown to reduce opioid requirement and reduce postoperative delirium in older adults. Methods We studied the use of post-operative intranasal dexmedetomidine in a retrospective study cohort of geriatric patients undergoing orthopedic surgery. Primary outcomes included alterations in heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR), peripheral oxygen saturation (SpO2), Modified Richmond Agitation and Sedation Score (mRASS), and opioid consumption following dexmedetomidine administration. Results We identified 23 patients with a mean (SD) age of 79.9 (7.5) years who received dexmedetomidine 100 mu g intranasally postoperatively. After dexmedetomidine administration, HR decreased by 10.4 (3.7) beats/min (95% CI 2.9-17.8; p = 0.004) and MAP by 16.2 (4.4) mmHg (95% CI 7.3-25.1; p < 0.001). HR decrease was significant at 2 h and MAP decrease at 1, 2, and 3 h following dexmedetomidine administration. Dexmedetomidine administration was associated with significant reductions in opioid consumption (p < 0.001) and mRASS score (p < 0.001). SpO(2) and RR remained unchanged. Conclusions These preliminary findings suggest that intranasal dexmedetomidine reduces opioid consumption without causing respiratory depression and may be used to treat postoperative restlessness, agitation, and pain in geriatric patients. However, hemodynamic effects of dexmedetomidine may require close observation for 3 hours following administration in older adult patients

Renal Replacement Techniques in Septic Shock

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection; it carries a risk for mortality, considerably exceeding that of a mere infection. Sepsis is the leading cause for acute kidney injury (AKI) and the requirement for renal replacement therapy (RRT) in intensive care unit (ICU) patients. Almost every second critically ill patient with sepsis will develop AKI. In septic shock, the dysregulated host response to infectious pathogens leads to a cytokine storm with uncontrolled production and release of humoral proinflammatory mediators that evoke cellular toxicity and promote the development of organ dysfunction and increased mortality. In addition to treating AKI, RRT techniques can be employed for extracorporeal adsorption of inflammatory mediators using specifically developed adsorption membranes, hemoperfusion sorbent cartridges or columns; these techniques are intended to decrease the level and early deleterious effects of circulating proinflammatory cytokines and endotoxins during the first hours and days of septic shock treatment, in order to improve patient outcomes. Several methods and devices, such as high cut-off membranes, the Oxiris(R)-AN69 membrane, CytoSorb(R) and HA380 cytokine hemoadsorption, polymyxin B endotoxin adsorption, and plasmapheresis have been examined in small study series or are under evaluation as ways of improving patient outcomes in septic shock. However, to date, the data on actual outcome benefits have remained controversial, as discussed in this review.</p

Predicting mortality in critically ill patients requiring renal replacement therapy for acute kidney injury in a retrospective single-center study of two cohorts

Half of the critically ill patients with renal replacement therapy (RRT) dependent acute kidney injury (AKI) die within one year despite RRT. General intensive care prediction models perform inadequately in AKI. Predictive models for mortality would be an invaluable complementary tool to aid clinical decision making. We aimed to develop and validate new prediction models for intensive care unit (ICU) and hospital mortality customized for patients with RRT dependent AKI in a retrospective single-center study. The models were first developed in a cohort of 471 critically ill patients with continuous RRT (CRRT) and then validated in a cohort of 193 critically ill patients with intermittent hemodialysis (IHD) as the primary modality for RRT. Forty-two risk factors for mortality were examined at ICU admission and CRRT initiation, respectively, in the first univariate models followed by multivariable model development. Receiver operating characteristics curve analyses were conducted to estimate the area under the curve (AUC), to measure discriminative capacity of the models for mortality. AUCs of the respective models ranged between 0.76 and 0.83 in the CRRT model development cohort, thereby showing acceptable to excellent predictive power for the mortality events (ICU mortality and hospital mortality). The models showed acceptable external validity in a validation cohort of IHD patients. In the IHD validation cohort the AUCs of the MALEDICT RRT initiation model were 0.74 and 0.77 for ICU and hospital mortality, respectively. The MALEDICT model shows promise for mortality prediction in critically ill patients with RRT dependent AKI. After further validation, the model might serve as an additional clinical tool for estimating individual mortality risk at the time of RRT initiation

Mortality and associated risk factors in patients with severe methanol or ethylene glycol poisoning treated with dialysis: a retrospective cohort study

Objective To compare the initial clinical course and data on 90-day mortality in adults with methanol (MET) or ethylene glycol (EG) poisoning treated with dialysis. Methods Data on patient demographics and clinical parameters at intensive care unit (ICU) admission and for the first 24 hours after dialysis initiation were collected, and 90-day outcome data were collected for patients with MET (n = 15) or EG (n = 13) poisoning treated with dialysis in this retrospective cohort study. Results In univariate analysis, patients with EG poisoning were older and they had lower hourly urine output during the first 24 hours after the initiation of dialysis. Six (46%) patients with MET poisoning and three (20%) patients with EG poisoning died within 90 days of ICU admission. A larger anion gap and lower pH, bicarbonate levels, base excess, and Glasgow Coma Scale scores on admission, as well as the need for mechanical ventilation, were associated with 90-day mortality. Conclusions Metabolic acidosis, a large anion gap, and an altered mental status on admission appear to be associated with mortality in MET or EG poisoning, and EG poisoning may be linked to lower urine output

Early restrictive fluid balance is associated with lower hospital mortality independent of acute disease severity in critically ill patients on CRRT

Fluid overload (FO) with coincident acute kidney injury has been associated with increased mortality. However, it is unclear whether FO is an independent determinant of mortality for disease severity. We aimed to explore whether the development of fluid balance (FB) during the first 72 h of continuous renal replacement therapy (CRRT) is independently associated with hospital mortality. All patients admitted to a single centre ICU requiring CRRT for at least 24 h between years 2010-2019 were included. Extracted data included patient demographics and clinical parameters including daily cumulative fluid balance (FBcum), lactate, SOFA score and vasoactive requirement at the initiation and during the first 72 h of CRRT. 399 patients were included in the analysis. Hospital survivors had a significantly lower FBcum at CRRT initiation compared to non-survivors (median 1382 versus 3265 ml; p = 0.003). Hourly fluid balance per bodyweight (FBnet) was lower in survivors at 0-24, 24-48 and 48-72 h after initiation of CRRT (p < 0.008 for all comparisons). In the survival analysis (analyzed with counting process model) significant time-dependent explanatory variables for hospital mortality were FBnet (per ml/kg/h: HR: 1.319, 95% CI 1.038-1.677, p = 0.02), lactate (HR: 1.086, 95% CI 1.030-1.145, p = 0.002) and SOFA score (per ml/kg/h: HR: 1.084, 95% CI 1.025-1.146, p = 0.005) during the first 72 h of CRRT. Even after careful adjustment for repeated measures of disease severity, FBnet during the first 72 h of CRRT remains independently associated with hospital mortality, in critically ill patients with AKI