The effect of dexmedetomidine and clonidine on the inflammatory response in critical illness: a systematic review of animal and human studies.

BACKGROUND: The α2 agonists, dexmedetomidine and clonidine, are used as sedative drugs during critical illness. These drugs may have anti-inflammatory effects, which might be relevant to critical illness, but a systematic review of published literature has not been published. We reviewed animal and human studies relevant to critical illness to summarise the evidence for an anti-inflammatory effect from α2 agonists. METHODS: We searched PubMed, the Cochrane library, and Medline. Animal and human studies published in English were included. Broad search terms were used: dexmedetomidine or clonidine, sepsis, and inflammation. Reference lists were screened for additional publications. Titles and abstracts were screened independently by two reviewers and full-text articles obtained for potentially eligible studies. Data extraction used a bespoke template given study diversity, and quality assessment was qualitative. RESULTS: Study diversity meant meta-analysis was not feasible so descriptive synthesis was undertaken. We identified 30 animal studies (caecal ligation/puncture (9), lipopolysaccharide (14), acute lung injury (5), and ischaemia-reperfusion syndrome (5)), and 9 human studies. Most animal (26 dexmedetomidine, 4 clonidine) and all human studies used dexmedetomidine. In animal studies, α2 agonists reduced serum and/or tissue TNFα (20 studies), IL-6 (17 studies), IL-1ß (7 studies), NFκB (6 studies), TLR4 (6 studies), and a range of other mediators. Timing and doses varied widely, but in many cases were not directly relevant to human sedation use. In human studies, dexmedetomidine reduced CRP (4 studies), TNFα (5 studies), IL-6 (6 studies), IL-1ß (3 studies), and altered several other mediators. Most studies were small and low quality. No studies related effects to clinical outcomes. CONCLUSION: Evidence supports potential anti-inflammatory effects from α2 agonists, but the relevance to clinically important outcomes is uncertain. Further work should explore whether dose relationships with inflammation and clinical outcomes are present which might be separate from sedation-mediated effects.

Quality and clinical supply considerations of Paediatric Investigation Plans for IV preparations-A case study with the FP7 CloSed project.

A Paediatric Investigation Plan (PIP) is a development plan that aims to ensure that sufficient data are obtained through studies in paediatrics to support the generation of marketing authorisation of medicines for children. This paper highlights some practical considerations and challenges with respect to PIP submissions and paediatric clinical trials during the pharmaceutical development phase, using the FP7-funded Clonidine for Sedation of Paediatric Patients in the Intensive Care Unit (CloSed) project as a case study. Examples discussed include challenges and considerations regarding formulation development, blinding and randomisation, product labelling and shipment and clinical trial requirements versus requirements for marketing authorisation. A significant quantity of information is required for PIP submissions and it is hoped that future applicants may benefit from an insight into some critical considerations and challenges faced in the CloSed project.

Analgesia e sedação da associação da clonidina e ropivacaína a 0, 75 por cento por via peridural no pós-operatório de colecistectomia aberta / Analgesia and sedation with epidural clonidine associated to 0. 75 percent ropivacaine in the postoperative period of open cholecystectomy

JUSTIFICATIVA E OBJETIVOS: A clonidina, quando administrada por via peridural, possui propriedades analgésicas e potencializa os efeitos dos anestésicos locais, ocorrendo, contudo, efeitos colaterais que incluem hipotensão arterial, bradicardia e sedação. O objetivo desse trabalho foi avaliar a analgesia e a sedação da clonidina associada à ropivacaína a 0,75 por cento no pós-operatório de colecistectomia aberta. MÉTODO: Participaram da pesquisa 30 pacientes, de ambos os sexos, com idades variando de 18 a 50 anos, peso entre 50 e 100 kg, estado físico ASA I e II, submetidos à colecistectomia, os quais foram distribuídos em dois grupos: Controle (GC), em que foi administrada ropivacaína a 0,75 por cento (20 ml), associada ao cloreto de sódio a 0,9 por cento (1 ml); Experimento (GE), em que foi injetada ropivacaína a 0,75 por cento (20 ml), associada à clonidina (1 ml = 150 'g). A analgesia e a sedação foram observadas 2, 6 e 24 horas após o término do ato operatório. RESULTADOS: A média de idade no GC foi de 41 anos e de 37 anos no GE. A média de peso foi de 67 kg no GC e de 64 kg no GE. A sedação no pós-operatório foi significativamente maior nos pacientes as 2 e 6 horas do grupo experimento. A analgesia foi observada em maior número de pacientes do grupo experimento, quando comparada ao grupo controle. CONCLUSÕES: A associação de clonidina e ropivacaína produziu analgesia mais duradoura e sedação em pacientes, nos horários de observação de 2 e 6 horas.

BACKGROUND AND OBJECTIVES: Epidural clonidine has analgesic properties and potentiates local anesthetic effects; there are, however, some side effects including: arterial hypotension, bradycardia and sedation. This study aimed at evaluating analgesia and sedation of clonidine associated to 0.75% ropivacaine in the postoperative period of open cholecystectomy. METHODS: Participated in this study 30 patients of both genders, aged 18 to 50 years, weighing 50 to 100 kg, physical status ASA I or II, submitted to cholecystectomy, who were distributed in two groups: Control Group (CG) received 0.75% ropivacaine (20 ml) with saline solution (1 ml); Experimental Group (EG) received 0.75% ropivacaine (20 ml) with clonidine (1 ml = 150 µg). Analgesia and sedation were observed at 2, 6 and 24 postoperative hours. RESULTS: Mean age was 41 yr in CG and 37 yr in EG. Mean weight was 67 kg in CG and 64 kg to EG. Postoperative sedation was significantly higher at 2 and 6 hours in the Experimental Group. Analgesia was observed in more EG patients as compared to Control Group. CONCLUSIONS: The association of clonidine and ropivacaine has produced longer analgesia and sedation at 2 and 6 hours of observation.

JUSTIFICATIVA Y OBJETIVOS: La clonidina, cuando administrada por vía peridural, posee propiedades analgésicas y potencializa los efectos de los anestésicos locales, ocurriendo por ello, efectos colaterales que incluyen hipotensión, bradicardia y sedación. El objetivo de ese trabajo fue evaluar la analgesia y la sedación de la clonidina asociada a la ropivacaína a 0,75% en el pos-operatorio de colecistectomia abierta. MÉTODO: Participaron de la pesquisa 30 pacientes, de ambos sexos, con edades variando de 18 a 50 años, con peso entre 50 y 100 kg, estado físico ASA I y II, sometidos a colecistectomia, y que fueron distribuidos en dos grupos: Control (GC), en que fue administrada ropivacaína a 0,75% (20 ml), asociada al clorato de sodio a 0,9% (1 ml); Experimento (GE), en que fue inyectada ropivacaína a 0,75% (20 ml), asociada a la clonidina (1 ml = 150 µg). La analgesia y la sedación fueron observadas 2, 6 y 24 horas después del término del momento operatorio. RESULTADOS: La media de edad en el GC fue de 41 años y de 37 años en el GE. La media de peso fue de 67 kg en el GC y de 64 kg en el GE. La sedación en el pos-operatorio fue significativamente mayor en los pacientes a las 2 y 6 horas del grupo de experimento. La analgesia fue observada en mayor número de pacientes del grupo de experimento, cuando comparada al grupo control. CONCLUSIONES: La asociación de clonidina y ropivacaína produjo analgesia que dura más, y sedación en pacientes, en los horarios de observación de 2 y 6 horas.