Improving animal welfare using continuous nalbuphine infusion in a long-term rat model of sepsis.

BACKGROUND: Sepsis research relies on animal models to investigate the mechanisms of the dysregulated host response to infection. Animal welfare concerns request the use of potent analgesics for the Refinement of existing sepsis models, according to the 3Rs principle. Nevertheless, adequate analgesia is often missing, partly because the effects of analgesics in this particular condition are unknown. We evaluated the use of nalbuphine, an opioid with kappa agonistic and mu antagonistic effects, in rats with and without experimental sepsis. METHODS: Male Wistar rats were anesthetized with isoflurane and instrumented with a venous line for drug administration. Arterial cannulation allowed for blood pressure measurements and blood sampling in short-term experiments of non-septic animals. Nalbuphine (or placebo) was administered intravenously at a dose of 1 mg/kg/h. Long-term (48 h) experiments in awake septic animals included repetitive clinical scoring with the Rat Grimace Scale and continuous heart rate monitoring by telemetry. Sepsis was induced by intraperitoneal injection of faecal slurry. Nalbuphine plasma levels were measured by liquid chromatography-high resolution mass spectrometry. RESULTS: In anesthetized healthy animals, nalbuphine led to a significant reduction of respiratory rate, heart rate, and mean arterial pressure during short-term experiments. In awake septic animals, a continuous nalbuphine infusion did not affect heart rate but significantly improved the values of the Rat Grimace Scale. Nalbuphine plasma concentrations remained stable between 4 and 24 h of continuous infusion in septic rats. CONCLUSIONS: In anaesthetised rats, nalbuphine depresses respiratory rate, heart rate, and blood pressure. In awake animals, nalbuphine analgesia improves animal welfare during sepsis.

Acute Toxicity Associated With the Recreational Use of the Novel Psychoactive Benzofuran N-methyl-5-(2 aminopropyl)benzofuran.

N-methyl-5-(2 aminopropyl)benzofuran (5-MAPB) is a novel psychoactive benzofuran, created by N-methylation of 5-(2-aminopropyl)benzofuran (5-APB), which shares structural features with methylenedioxymethamphetamine (MDMA). To our knowledge, no case of 5-MAPB-related toxicity has been published in the scientific literature. We report a case of oral 5-MAPB exposure confirmed by liquid chromatography-tandem mass spectrometry in a 24-year-old previously healthy white man. Observed symptoms and signs such as paleness, cold and clammy skin, hypertension, elevated high-sensitive troponin T level, tachycardia, ECG change, diaphoresis, mild hyperthermia, mydriasis, tremor, hyperreflexia, clonus, agitation, disorientation, hallucinations, convulsions, reduced level of consciousness, and creatine kinase level elevation (305 IU/L) were compatible with undesired effects related to 5-APB or MDMA exposure. Signs and symptoms resolved substantially within 14 hours with aggressive symptomatic treatment, including sedation with benzodiazepines, external cooling, analgesia and sedation with fentanyl-propofol, and treatment with urapidil, an α-receptor-blocking agent. 5-MAPB showed first-order elimination kinetics with a half-life of 6.5 hours, comparable to the half-life of MDMA. According to the chemical structure, this case report, and users' Web reports, 5-MAPB appears to have an acute toxicity profile similar to that of 5-APB and MDMA, with marked vasoconstrictor effect.

Analgesia in clinically relevant rodent models of sepsis.

Postoperative analgesia in rodent sepsis models has been considerably neglected in the past. However, intentions to model clinical practice, increasing awareness of animal ethics, efforts to apply the 3Rs (replacement, reduction, refinement), and stricter legislation argue for a change in this respect. In this review, we describe different concepts of analgesia in rodent models of sepsis focusing on opioid agonists as well as non-opioid analgesics. Advantages and pitfalls in study design and side-effects are discussed. Score sheets should be used to adapt analgesia or to terminate experiments using humane endpoints. Further research is needed to differentiate behavioral changes caused by sepsis and pain or as a consequence of analgesia. Information on the efficacy of analgesia in sepsis models is scarce. Hence, studies are needed to identify the best ways to reduce suffering of research animals and thereby optimize the clinically relevant rodent models of sepsis.

Shock Management for Cardio-surgical Intensive Care Unit Patient: The Silver Days.

Shock in cardio-surgical intensive care unit (ICU) patients requires prompt identification of the underlying condition and timely therapeutic interventions. Management during the first 6 hours, also referred to as "the golden hours", is of paramount importance to reverse the shock state and improve the patient's outcome. The authors have previously described a state-of-the-art diagnostic work-up and discussed how to optimise preload, vascular tone, contractility, heart rate and oxygen delivery during this phase. Ideally, shock can be reversed during this initial period. However, some patients might have developed multiple organ dysfunction, which persists beyond the first 6 hours despite the early haemodynamic treatment goals having been accomplished. This period, also referred to as "the silver days", is the focus of this review. The authors discuss how to reduce vasopressor load and how to minimise adrenergic stress by using alternative inotropes, extracorporeal life-support and short acting beta-blockers. The review incorporates data on fluid weaning, safe ventilation, daily interruption of sedation, delirium management and early rehabilitation. It includes practical recommendations in areas where the evidence is scarce or controversial. Although the focus is on cardio-surgery ICU patients, most of the considerations apply to critical ill patients in general.

Diagnostic performance of reproducible chest wall tenderness to rule out acute coronary syndrome in acute chest pain: a prospective diagnostic study.

OBJECTIVES: Acute chest pain (ACP) is a leading cause of hospital emergency unit consultation. As there are various underlying conditions, ranging from musculoskeletal disorders to acute coronary syndrome (ACS), thorough clinical diagnostics are warranted. The aim of this prospective study was to assess whether reproducible chest wall tenderness (CWT) on palpation in patients with ACP can help to rule out ACS. METHODS: In this prospective, double-blinded diagnostic study, all consecutive patients assessed in the emergency unit at the University Hospital Zurich because of ACP between July 2012 and December 2013 were included when a member of the study team was present. Reproducible CWT on palpation was the initial step and was recorded before further examinations were initiated. The final diagnosis was adjudicated by a study-independent physician. RESULTS: 121 patients (60.3% male, median age 47 years, IQR 34-66.5 years) were included. The prevalence of ACS was 11.6%. Non-reproducible CWT had a high sensitivity of 92.9% (95% CI 66.1% to 98.8%) for ACS and the presence of reproducible CWT ruled out ACS (p=0.003) with a high negative predictive value (98.1%, 95% CI 89.9% to 99.7%). Conversely non-reproducible CWT ruled in ACS with low specificity (48.6%, 95% CI 38.8% to 58.5%) and low positive predictive value (19.1%, 95% CI 10.6% to 30.5%). CONCLUSIONS: This prospective diagnostic study supports the concept that reproducible CWT helps to rule out ACS in patients with ACP in an early stage of the evaluation process. However, ACS and other diagnoses should be considered in patients with a negative CWT test. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov: NCT01724996.

Shock Management for Cardio-surgical ICU Patients - The Golden Hours.

Postoperative shock following cardiac surgery is a serious condition with a high morbidity and mortality. There are four types of shock: cardiogenic, hypovolemic, obstructive and distributive and these can occur alone or in combination. Early identification of the underlying diseases and understanding of the mechanisms at play are key for successful management of shock. Prompt resuscitation measures are necessary to reverse the shock state and avoid permanent organ dysfunction or death. In this review, the authors focus on the management during the first 6 hours of shock (the 'golden hours'). They discuss how to optimise preload, vascular tone, contractility, heart rate and oxygen delivery. The review incorporates the findings of recent trials on early goal-directed therapy and includes practical recommendations in areas in which the evidence is scare or controversial. While the review focuses on cardio-surgical patients, the suggested treatment algorithms might be usefully expanded to other critically ill patients with shock arising from other causes.

Sinusectomy for primary pilonidal sinus: less is more.

BACKGROUND: Wide excision with secondary wound healing is a frequently performed surgical procedure for pilonidal sinus. This intervention requires general anesthesia and has a wound healing time of up to several months with a long time to return to work. Sinusectomy of the track is an alternative operation. We here describe the long-term outcome of 257 patients operated between 2001 and 2010. METHODS: Sinusectomy consisted of a selective minimal invasive excision of the sinus after marking the track with methylene blue. Data were collected retrospectively with questionnaires and telephone survey. The main endpoints of the study were recurrence and time off work. RESULTS: With a median follow-up of 3.6 years, the overall recurrence rate was 7%. The median time to return to work was 7 days. The proportion of sinusectomies performed under local anesthesia increased from 59% to 93%. Consistently, the proportion of patients treated in 1-day surgery setting increased from 53% to 93%. One-day surgery had a clear impact on time to return to work in uni- and multivariate analyses (HR 1.959 {1.224, 3.137}, P = .005). CONCLUSION: Sinusectomy for pilonidal sinus can be performed with a low recurrence rate. An outpatient setting, including operations under local anesthesia, allows a fast return to normal activity. Sinusectomy should become the first choice for primary non-infected symptomatic pilonidal sinus.

Vascular dysfunction of brachial artery after transradial access for coronary catheterization: impact of smoking and catheter changes.

OBJECTIVES: The aim of this study was to investigate the effect of diagnostic transradial catheterization on vascular function of upstream brachial artery (BA). BACKGROUND: The transradial access has recently become an alternative to transfemoral cardiac catheterization. A potential caveat of this approach lies in possible sustained physical radial artery (RA) damage. METHODS: We studied 30 patients (age 61 +/- 11 years) undergoing diagnostic coronary angiography with the transradial access (5-F). Endothelium-dependent, flow-mediated vasodilation (FMD) was measured before and at 6 and 24 h after catheterization of the right-sided RA and BA with high-resolution ultrasound. The left-sided RA served as a control. RESULTS: Transradial catheterization significantly decreased FMD in the RA (overall mean 8.5 +/- 1.7% to 4.3 +/- 1.6%) and the upstream BA (overall mean 4.4 +/- 1.6% to 2.9 +/- 1.6%) at 6 h. Subgroup analysis showed that FMD of both arteries at 6 h was significantly lower in active smokers and that it only remained impaired at 24 h in this group, whereas nonsmoker FMD fully recovered. The degree of BA but not RA FMD dysfunction was related to the number of catheters used, with no change after 2 catheters, 1.9 +/- 1.2% decrease (6 h) and recovery (24 h) after 3 catheters, and 3.9 +/- 1.2% decrease (6 h) without recovery (24 h) after 4 to 5 catheters. The RA dysfunction correlated with the baseline diameter. The contralateral control RA exhibited no change ruling out systemic effects. CONCLUSIONS: Transradial catheterization not only leads to dysfunction of the RA but also the upstream BA, which is more severe and sustained in smokers and with increasing numbers of catheters.