Italian Intersociety Recommendations on pain management in the emergency setting (SIAARTI, SIMEU, SIS 118, AISD, SIARED, SICUT, IRC).

BACKGRAUND: Pain is the primary reason for admission to the Emergency Department (ED). However, the management of pain in this setting is often inadequate because of opiophagia, fear of excessive sedation, and fear of compromising an adequate clinical assessment. METHODS: An intersociety consensus conference was held in 2010 on the assessment and treatment of pain in the emergency setting. This report is the Italian Intersociety recommendations on pain management in the emergency department setting. RESULTS: The list of level A recommendations includes: 1) use of IV acetaminophen for opioid sparing properties and reduction of opioid related adverse events; 2) ketamine-midazolam combination preferred over fentanyl-midazolam fentanyl-propofol in pediatric patients; 3) boluses of ketamine IV (particularly in the population under the age of 2 years and over the age of 13) can lead to impairment of the upper airways, including the onset of laryngospasm, requiring specific expertise and skills for administration; 4) the use of ketamine increases the potential risk of psychomotor agitation, which can happen in up to 30% of adult patients (this peculiar side effect can be significantly reduced by concomitant systemic use of benzodiazepines); 5) for shoulder dislocations and fractures of the upper limbs, the performance of brachial plexus block reduces the time spent in ED compared to sedation; 6) pain relief and the use of opioids in patients with acute abdominal pain do not increase the risk of error in the diagnostic and therapeutic pathway in adults; 7) in newborns, the administration of sucrose reduces behavioural responses to blood sampling from a heel puncture; 8) in newborns, breastfeeding or formula feeding during the procedure reduces the measures of distress; 9) in pediatric patients, non-pharmacological techniques such as distraction, hypnosis and cognitive-behavioural interventions reduce procedural pain caused by the use of needles; 10) in pediatric patients, preventive application of eutectic mixtures of prilocaine and lidocaine allows arterial and venous samples to be taken in optimum conditions; 11) in pediatric patients, the combination of hypnotics (midazolam) and N2O is effective for procedural pain, but may be accompanied by loss of consciousness. CONCLUSION: The diagnostic-therapeutic pathway of pain management in emergency should be implemented, through further interdisciplinary trials, in order to improve the EBM level of specific guidelines.

Study of skin vasomotion during phollicular and luteal phase in young healthy women.

The aim of this study was to evaluate if changes in female sex hormones associated to follicular phase (FP) and luteal phase (LP) may affect skin vasomotion in women with evidence of ovulatory cycle. Nine healthy non-smoker women aged 25+/-4 years, with regular menstrual cycle of 28+/-2 days and evidence of ovulation (indicated by a mid-luteal serum progesterone concentration > 5 ng/ml) (group-1) and six healthy non-smoker healthy women aged 24+/-2 years with evidence of an-ovulatory cycle (group-2) were enrolled in the study. At the times 1 (7th-10th day from the beginning of the last menstrual cycle) and at the time 2 (18th-22th day from the beginning of the last menstrual cycle) forearm skin vasomotion was investigated by means of spectral Fourier analysis of the skin laser Doppler flowmetry (LDF) tracing registered under basal conditions and following acetylcholine (ACh) iontophoresis. The power spectral density (PSD) of the 0.01-0.02, 0.02-0.06 and 0.06-0.2 Hz LDF tracing frequency intervals (related to endothelial-, sympathetic- and myogenic-dependent vasomotion, respectively) was measured in PU2 (LDF perfusion unit)/Hz (1 PU = 10 mV). At the same times skin blood flux response (percentage change from baseline) to ACh and to sodium nitroprusside (SNP) iontophoresis was also investigated. Basal and ACh-stimulated skin vasomotion did not significantly differ between time 1 and time 2 in PSD of the three frequency intervals investigated in both groups, as well as between the two groups at each time of investigation. Similarly, no significant changes were observed in skin vasodilator response to ACh and SNP iontophoresis between time 1 and 2 in each group. These results suggest that the female sex hormone changes associated to the FP and LP in young women with ovulatory cycle do not affect basal and ACh stimulated skin vasomotion as well as the endothelial- and non-endothelial-dependent skin vasoreactivity.

Skin blood flowmotion and microvascular reactivity investigation in hypercholesterolemic patients without clinically manifest arterial diseases.

Fourier spectral analysis of forearm skin laser Doppler flowmetry (LDF) signal was performed in fifteen hypercholesterolemic patients (HP), without clinically manifest arterial diseases, and in fifteen age-matched healthy control subjects (CS), in order to investigate skin blood flowmotion (SBF). The LDF frequency intervals studied were: 0.01-1.6 Hz total spectrum, as well as 0.01-0.02 Hz (endothelial), 0.02-0.06 Hz (sympathetic), 0.06-0.2 Hz (myogenic), 0.2-0.6 Hz (respiratory) and 0.6-1.6 Hz (cardiac). Skin microvascular reactivity (MVR) to acetylcholine (ACh) and to sodium nitroprusside (SNP) iontophoresis was also investigated. HP showed a lower post-ACh increase in power spectral density (PSD) of the 0.01-0.02 Hz SBF subinterval compared to CS (1.80+/-1.73 PU(2)/Hz vs 3.59+/-1.78 PU(2)/Hz, respectively; p<0.005), while they did not differ in MVR from CS. In eleven HP the 0.01-0.02 Hz SBF subinterval showed a higher post-ACh PSD increase near to the statistical significance after 10 weeks of rosuvastatin therapy (10 mg/day) compared to pretreatment test (3.04+/-2.95 PU(2)/Hz vs 1.91+/-1.94 PU(2)/Hz; p=0.07). The blunted post-ACh increase in PSD of the 0.01-0.02 Hz SBF subinterval in HP suggests a skin endothelial dysfunction in these patients. This SBF abnormality showed a tendency to improve after rosuvastatin therapy in eleven treated patients.

Blunted increase of digital skin vasomotion following acetylcholine and sodium nitroprusside iontophoresis in systemic sclerosis patients.

OBJECTIVES: To test the hypothesis that finger skin vasomotion (FSV), a known factor influencing microvascular blood flow motion, is impaired in SSc patients. Possible relationships between FSV abnormalities and the severity and/or activity of SSc were also investigated. METHODS: FSV was investigated by means of spectral Fourier analysis of finger skin laser Doppler flowmetry (LDF) tracing, recorded before and following acetylcholine (ACh) or sodium nitroprusside (SNP) iontophoresis in 26 SSc patients and in 20 age-matched healthy controls. The power spectral density (PSD) of the 0.01-0.02, 0.02-0.06 and 0.06-0.2 Hz LDF oscillations (related to endothelial-, sympathetic- and myogenic-dependent FSV, respectively) was measured in PU(2) (perfusion units)/Hz. RESULTS: Compared with controls, SSc patients exhibited a significantly lower post-ACh and/or post-SNP percentage increase in PSD of 0.01-0.02 Hz (492 +/- 297% vs 283 +/- 167%; P < 0.005), of 0.02-0.06 Hz (336 +/- 205% vs 239 +/- 170%; P < 0.05) and of 0.06-0.2 Hz (223 +/- 91% vs 194 +/- 227%; P < 0.01) skin LDF oscillations. The post-SNP normalized PSD value of the 0.01-0.02 Hz and of the 0.02-0.06 Hz LDF oscillations was negatively related to SSc severity index (r = -0.407, P < 0.05 and r = -459, P < 0.05, respectively). CONCLUSIONS: This study showed a selective abnormality of the endothelial, sympathetic and myogenic-dependent FSV in SSc patients, consistent with a parallel endothelial, sympathetic and myogenic macrovascular dysfunction. This study also suggests a possible role of endothelial and sympathetic dysfunction in the progression of SSc.

Post-ischaemic peak flow and myogenic flowmotion component are independent variables for skin post-ischaemic reactive hyperaemia in healthy subjects.

The aim of this study was to clarify whether the post-ischaemic amplification of skin blood flowmotion (SBF) influences the extent of skin post-ischaemic hyperaemia. Forearm skin perfusion was measured by means of laser Doppler flowmetry (LDF) and forearm SBF was examined using Fourier analysis of LDF signal, under basal conditions and following forearm ischaemia in 50 healthy subjects. Power spectral density (PSD) of SBF total spectrum (0.009-1.6 Hz), as well of the frequency intervals (FI) related to endothelial (0.009-0.02 Hz), sympathetic (0.02-0.06 Hz), myogenic (0.06-0.2 Hz), respiratory (0.2-0.6 Hz) and cardiac (0.6-1.6 Hz) activity was measured in PU(2) (LDF perfusion unit)/Hz. Multiple regression analysis evaluated whether post-ischaemic peak-flow, as an indicator of shear stress, or post-ischaemic SBF independently affected the post-peak-flow hyperaemia calculated as corrected area under the LDF curve (C-AUC). Following ischaemia, we observed a statically significant increase in skin perfusion (from basal of 11.7+/-5.8 PU to peak flow of 62.3+/-41.4 PU, p<0.0000005) and in PSD of SBF total spectrum (p<0.01) as well of the different FI considered (p<0.005 for the endothelial and myogenic FI; p<0.05 for the sympathetic, respiratory and cardiac FI) compared to baseline. Multiple regression analysis showed that peak flow and post-ischaemic SBF component of myogenic origin were significant independent variables for the C-AUC (p=0.0000001 and p=0.009, respectively). These findings suggest that not only increased shear stress but also post-ischaemic amplification of myogenic SBF component independently contributes to the more prolonged phase of post-ischaemic skin re-perfusion in healthy subjects.

Absent post-ischemic increase of blood flowmotion in the cutaneous microcirculation of healthy chronic cigarette smokers.

The aim of the study was to investigate whether chronic cigarette smoke habit is associated with changes of laser Doppler (LD) skin blood flowmotion (SBF). We performed spectral analysis of skin forearm LD signal detected by a LD flowmetry (Periflux PF4, Perimed, Sweden) before and during forearm post-ischemic hyperaemia, in 14 healthy chronic smoker subjects and 14 age and sex matched nonsmoker subjects. Forearm skin ischemia was obtained by a pneumatic cuff, positioned at the right arm and inflated for 3 minutes to 30 mmHg above systolic blood pressure. Power spectral density (PSD) of the SBF total spectrum (0.009-1.6 Hz), as well as 0.009-0.02 Hz , 0.02-0.06 Hz, 0.06-0.2 Hz, 0.2-0.6 Hz and 0.6-1.6 Hz frequency intervals (FI), referred to endothelial, sympathetic, myogenic, respiratory and heart activity, respectively, were measured in LD conventional perfusion units (PU)/Hz. Smokers showed a basal SBF total spectrum PSD mean values not significantly different from nonsmokers (2.14+/-1.58 PU/Hz and 1.93+/-1.35 PU/Hz, respectively). Following ischemia, PSD mean value of SBF total spectrum, as well of five FI considered, significantly increased in nonsmokers (p<0.01), while it did not significantly change in smokers. Smokers and nonsmokers did not differ in basal and post-ischemic skin LD perfusion mean values. The absent post-ischemic increase of the SBF and of its FI related to endothelial and myogenic activity in smokers can be an early sign of skin microcirculatory impairment, suggesting an endothelial and smooth muscle skin microvascular dysfunction associated with the chronic smoking habit.

Skin microcirculatory effect of exogenous calcitonin gene-related peptide (CGRP) evaluated by laser Doppler flowmetry coupled with iontophoresis in healthy subjects.

The aim of our study was to evaluate the feasibility of laser Doppler flowmetry (LDF) coupled with iontophoresis in exploring the skin vasodilator activity of exogenous calcitonin gene-related peptide (CGRP) in healthy subjects and to investigate the mechanisms involved in the skin vasodilator activity of this peptide. Forearm skin blood perfusion was measured in conventional perfusion unit (PU; 1 PU=10 mV), using a LDF apparatus (Periflux PF4001, Perimed, Sweden), before and following exogenous CGRP dissolved in distilled water (0.02%) or pure saline iontophoresis. Different iontophoresis protocols were used in a preliminary dose finding study in six subjects. Two pulses (0.1 mA for 30 s each) of anodal CGRP or saline iontophoresis were used in the definitive study in 20 subjects. Power spectral density (PSD) of skin blood flowmotion frequency intervals (FI), related to endothelial (0.009-0.02 Hz), sympathetic (0.02-0.06 Hz), myogenic (0.06-0.2 Hz), respiratory (0.2-0.6 Hz) and heart (0.6-1.6 Hz) activities, was also measured in PU(2)/Hz, by means of spectral analysis of the skin LDF signal registered before and following iontophoresis of CGRP or saline in the definitive study. A significantly higher per cent increase in skin perfusion compared to baseline was observed following CGRP than saline iontophoresis (548+/-369% vs. 326+/-192%, p<0.05), with higher hyperaemic response to pure saline than CGRP iontophoresis in only five subjects. A significant increase (p<0.05) in PSD mean value of the five FI considered, was also observed following CGRP iontophoresis, while saline iontophoresis elicited a significant increase (p<0.05) only in PSD of the FI related to endothelial, respiratory and heart activity. These findings demonstrated that LDF coupled with iontophoresis is a feasible method in evaluating the vasodilator effect of exogenous CGRP in human skin and suggest that this peptide directly or indirectly induces a smooth muscle vascular cells and sympathetic fibres stimulation.

Nutritive blood flow affects microdialysis O/I ratio for [(14)C]ethanol and (3)H(2)O in perfused rat hindlimb.

Changes in the microdialysis outflow-to-inflow (O/I) ratio for [(14)C]ethanol and (3)H(2)O were determined in the perfused rat hindlimb after increases and decreases in nutritive flow mediated by the vasoconstrictors norepinephrine (NE) and serotonin (5-HT), respectively. Microdialysis probes (containing 10 mM [(14)C]ethanol and (3)H(2)O pumped at 1 or 2 microl/min) were inserted through the calf of the rat. Hindlimb perfusion flow rate was varied from 6 to 56 ml x min(-1) x 100 g(-1) in the presence of NE, 5-HT, or saline vehicle. The O/I ratios for both tracers were determined at each perfusion flow rate, as was perfusion pressure, oxygen uptake (a surrogate indicator of nutritive flow), and lactate release. Both tracers showed a decreased O/I ratio as hindlimb perfusion flow was increased, with [(14)C]ethanol being higher than (3)H(2)O. NE decreased the O/I ratio compared with vehicle, and 5-HT increased it for both tracers and both microdialysis flow rates. We conclude that the microdialysis O/I ratio, while able to detect changes in total flow, is also sensitive to changes in nutritive and nonnutritive flow, where the latter still extracts tracer, but less than the former.

Na+ channel and Na+-K+ ATPase involvement in norepinephrine- and veratridine-stimulated metabolism in perfused rat hind limb.

In the constant flow perfused rat hind limb, norepinephrine (NE) evoked increases in oxygen uptake (VO2) and lactate efflux (LE) were inhibited by the cardiac glycoside ouabain (1 mM), without interrupting the NE-mediated vasoconstriction. The membrane labilizer veratridine, previously shown to increase VO2 and LE, without increasing perfusion pressure, was also shown to be inhibited by the cardiac glycoside ouabain, as well as by the ouabain analogues digitoxin and digoxin. The stimulatory actions of veratridine on VO2 were inhibitable by low doses of the specific sodium channel blocker tetrodotoxin (TTX), while NE effects were unaffected, suggesting that NE may be acting via a TTX-insensitive sodium channel. It is concluded that agents such as NE (a vasoconstrictor) or veratridine (a membrane labilizer), which stimulate VO2 in the perfused rat hind limb, do so by increasing Na+ influx. The observed increases in oxygen consumption and LE are due to Na+-K+ ATPase activity to pump Na+ out of the cell at the expense of ATP turnover. Energy dissipation due to Na+ cycling may be a form of facultative thermogenesis attributable to NE that can be stimulated by membrane labilizers such as veratridine in the constant flow perfused rat hind limb.