Background. We studied the effect of fast induction of cardiac arrest with denosine on myocardial bax and bcl-2 expression. Methods and Results. 40 elective CABG patients were allocated into two groups. The adenosine group (n = 20) received 250 μg/kg adenosine into the aortic root followed by blood potassium cardioplegia. The control group received potassium cardioplegia in blood. Bcl-2 and bax were measured. Bax was reduced in the postoperative biopsies  in the control group. Bcl-2 showed a reducing tendency . After the adenosine treatment, the expression of both bax  and bcl-2  remained unaltered after the operation. Conclusion. Open heart surgery is associated with rapid reduction in the expression of apoptosis regulating genes bax and bcl-2. Fast Adenosine induction abolished changes in their expression. Apoptosis has been considered as one of the mechanisms of cell loss during ischemia/reperfusion (I/R) injury –3. The pMyocardial upregulation of the proapoptotic gene bax and reduction of both bcl-2 and bcl-2/bax ratios are predisposing the cardiomyocytes to apoptosis , 7. TheiInjection of adenosine into the aortic root followed by blood cardioplegia solution after cross-clamping, produces significantly faster cardiac standstill in patients with severe coronary artery disease , 16. AdeThe main motive behind our present study is based on the previous findings , 23 reprThe aim of this study was to determine whether cardiac surgery using cardiopulmonary bypass (CPB) is associated with changes in the expression of apoptosis-regulating genes bax and bcl-2 in humans. We also studied whether more rapid induction of myocardial arrest by a single bolus injection of adenosine followed by potassium blood cardioplegia modifies their expression. We hypothesized that analysis of bax and bcl-2 changes in genes expression might serve a marker of myocardial injury and success of cardioprotection early after cardiac surgery with cardioplegic arrest.The main cohort of this study included 40 patients who were scheduled for an elective CABG procedure using on-pump CPB technique. The exclusion criteria were diabetic patients with sulfonylurea medication, unstable angina, recent myocardial infarction within the last month, redo cardiac operation, preoperative diagnosis of asthma, chronic obstructive pulmonary disease; the patients did not have a history of chronic renal or hepatic diseases, and their values of creatinine  and aP-TT-INR  were within normal range. Patients with poor left ventricular function (ejection fraction EF ≤ 30), valvular disease, and those receiving corticosteroids were also considered not eligible. After institutional approval by the Ethics Committee of Tampere University Hospital, the protocol for this prospective randomized, double blind, placebo-controlled study was reviewed by National Agency for Medicines, Finland. All 40 patients gave their informed consent.In our previous publication  we had cμg/kg), and cisatracurium. Sufentanil infusion was continued with a rate of 0.03–0.05 μg/kg/min. Sevoflurane was used as the main anaesthetic agent throughout the operation, and also provided during the cardiopulmonary perfusion with a vaporiser attached to the fresh gas inlet.A radial artery line and a pulmonary artery catheter were inserted for haemodynamic monitoring. Anaesthesia was induced with propofol (0.5–1.0 mg/kg), sufentanil  with nonpulsative flow with a membrane oxygenator. The circuit was primed with 1500 mL of Ringer's acetate. The proximal anastomoses were constructed during a single cross-clamping period. μg/kg adenosine into the aortic root just after cross-clamping. This dose was chosen in view of a pilot study to be the lowest effective dose to stop the myocardium. The plan is to use Adenosine as a single bolus dose to allow the evaluation of adenosine not only as a pretreatment during the reperfusion but also as a maintenance dose of myocardial protection during ischemia and reperfusion.Patients randomization was between January 2006 and May 2007. Patients were allocated into two groups. In the adenosine group, 20 patients received 250 20 patients in the control group received normal saline as placebo. All patients received standard blood cardioplegia delivered through antegrade route. The basal CP concentrations were identical in both groups, except for the study medication. Concentrations of potassium and magnesium depend on the mixing ratio of cardioplegia rollers. Ratio 1 : 4 is used for the induction, 1 : 8 for the subsequent infusions and also for the warm terminal infusion.Total volume of cardioplegia (CP) was not recorded. Cardioplegia was administered by means of time, pressure, and flow (according to the guidelines by Dr. Buckberg). CP was infused via antegrade route with pressure of 60–80 mmHg. Maximal flow was 300 mL/min. Duration of the induction infusion was three minutes. Additional infusions after each distal anastomosis were for one minute, and the final warm infusion was given for three minutes. The effect of adenosine is known to be dependent on the temperature . TherefoFrom each patient, we harvested two samples from the right atrium at two different times. The first one was obtained before cross-clamping as the baseline biopsy and the second from the same location just before CPB was discontinued. Myocardial samples (5–10 × 3 mm) were immediately frozen in liquid nitrogen for assessment of gene expression.®) stitches even when no bleeding occurred. Myocardial tissue (5–10 × 3 mm) was immediately frozen in liquid nitrogen for histological studies.Two samples of left ventricular apex were harvested in both groups. The first sample was taken immediately after CPB was established by oblique introduction of Tru-Cut needle (PRECISA TM 14G X 150 mm) into the left ventricle apical wall. The second sample was taken from the same location by the same needle before weaning from CPB. The puncture sites were secured with small 4-0 prolene (Ethicon®) according to manufacturer's instructions. The RNA concentration was determined using spectrophotometry. Total RNA (1 μg) from each sample was incubated with equal amount of random hexamers (Promega™) at 70°C for 10 minutes and then cooled on ice for 5 minutes. Complementary DNA (cDNA) was synthesized in a mixture containing M-MLV Reverse Transcriptase RNase H Minus-enzyme (200 U), Recombinant RNasin Ribonuclease Inhibitor (40 U), dNTP mix (25 mM each), M-MLV RT 5x buffer, and Nuclease-free water . Mixtures were incubated at room temperature for the initial 10 minutes, then at 50°C for the final 50 minutes. Finally, the reaction was inactivated by heating for 5 minutes at 95°C.Atria samples were homogenized and total RNA was extracted with Trizol reagent  used in real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay. In order to prevent the amplification of contaminating genomic DNA, primer pairs were located in different exons. Housekeeping gene 18S rRNA was used as an endogenous control .Sequences of the oligonucleotide primers and probes used in real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay were the same that used for bax and bcl-2  , specific probe (100 nM), and TaqMan® Universal PCR Master Mix. Primer and probe concentrations for 18S were 50 nM and 200 nM, respectively. After incubation at 50°C for 2 minutes and denaturing at 95°C for 10 minutes, PCR was carried out, 50 cycles of 95°C for 15 seconds and 60°C for 1 minute. All RT-PCR reactions were run as a duplicate.The quantitative real-time RT-PCR was performed using Applied Biosystems 7500 RT-PCR system and TaqmanQuantification of gene expression was carried out by using relative standard curve method. Briefly, standard curves for each plate were generated using serial dilutions of cDNA synthesized from human tonsil tissue RNA. The amounts of both target and endogenous control cDNA in each sample were calculated relative to the standards. To eliminate the variation of total cDNA quantity in each sample, the results are expressed as a ratio of the target gene to the endogenous control.Apoptosis was detected using the terminal transferase mediated ddUTP nick end-labeling (TUNEL) assay, as previously described , 27. In U Test was used to distinguish demographic differences in means between the groups. Continuous variables were analyzed by analysis of variance (ANOVA) for repeated measures. Logarithmic transformation, median and quarter analysis methods were used when the variables were not normally distributed. Statistical significance was attributed to P value <.05.Statistical analysis was performed using SPSS for Windows software, version 9.0 . The Mann-Whitney The study cohort included 40 patients between the ages of 46 and 73 years, 90% of them were male patients . Twenty P = .002). Expression of bcl-2 showed a similar reduction tendency (P = .07). However, in contrast to the control group, expression of both bax and bcl-2 remained unaltered before and after the operation in the adenosine treatment group (P = .45 and .47). There were no significant differences in the level of bax/bcl-2 ratio expression in either pre- or postoperative samples in the control and adenosine groups.As shown in As shown in Values are presented as median values and standard deviation. “Before” refers to before cross-clamp application and “After” refers to after cross-clamp removal and just before CPB discontinuation.We found a decrease in apoptosis regulating genes in right atria samples obtained immediately after reperfusion compared to preischemic samples in patients undergoing CABG. Interestingly, expression remained stable in patients randomized to adenosine treatment during cardioplegia. Also, in the adenosine group, the bax/bcl-2 ratio decreased more than in the control group, although the decrease was not statistically significant. Previously, in a canine model, adenosine reduced apoptosis induced by I/R injury. This reduction was associated with enhanced expression of antiapoptotic bcl2 genes. Adenosine also reduced expression of proapoptotic bax gene in the peri-infarct myocardium . Our resIn parallel with the observed changes in the expression of apoptosis-regulated genes, the amount of apoptotic cardiomyocytes as detected with the TUNEL-assay in the left ventricular samples of the patients appeared to be reduced in the adenosine treated group as reported earlier . HoweverTherefore, further methodological validation and development is still needed. Future studies should explore at least the use of other genes as potential markers as well as optimal timing of tissue sampling. In the overall picture, as expressed in Some previous studies which were focusing on the effect of fast adenosine induction of myocardial arrest showed the postoperative clinical improvement in this group of patients . As we rIn conclusion, cardioplegic arrest during CABG surgery results in changes in apoptosis-regulating genes. The change is detectable in myocardial tissue samples obtained very early after reperfusion and therefore, this method may allow assessment of the quality of myocardial protection.


To study the effectiveness and safety of budesonide/formoterol (Symbicort®) Maintenance And Reliever Therapy , a simplified management approach with one inhaler compared with conventional best practice (CBP) with multiple inhalers in patients with persistent asthma.Open-label randomised controlled parallel group trial, 6-month treatment.2-agonist.A total of 908 patients ≥ 12 years of age, with persistent asthma receiving treatment with inhaled corticosteroids (ICS), either alone or in conjunction with long-acting βTime to first severe asthma exacerbation and number of severe asthma exacerbations.No difference between groups was seen in time to first severe exacerbation (p = 0.75). Exacerbation rates were low in both groups. A total of 12 patients in the Symbicort SMART® group experienced a total of 14 severe asthma exacerbations, and 19 patients in the CBP group experienced a total of 25 severe asthma exacerbations . The mean daily dose of ICS expressed in BDP equivalent was significantly lower in the Symbicort SMART® group (including as-needed use) vs. in the CBP group . Mean scores in Asthma Control Questionnaire, 5 question version improved significantly in the SMART group compared with the CBP group (p = 0.0026). Symbicort SMART and CBP were equally well tolerated.The mean drug cost/patient/month was significantly lower for the patients in the Symbicort SMART group compared with patients receiving CBP .In Belgian patients, a simplified regimen using budesonide/formoterol maintenance and reliever therapy was at least as effective at improving clinical control compared with CBP with a significantly lower ICS dose and significantly lower drug costs. Although SMART strategy has proved its efficacy and safety in asthma management in controlled studies, data showing this concept may still be operating in real clinical practice are still sparse.Our study shows that, in a setting close to real clinical practice, Symbicort SMART is at least as effective as best conventional practice in controlling asthma but with a significantly lower dose of ICS and lower drug costs.The primary goals of asthma treatment are to avoid severe asthma exacerbations, to control symptoms and to maintain normal lung function with the lowest effective dose of medication so that unnecessary adverse effects can be avoided. Global Initiative for Asthma (GINA) guidelines recommend a stepwise approach for asthma therapy that is based on achieving asthma control. Patients with persistent asthma, not adequately controlled by maintenance therapy with a low-to-medium dose of inhaled corticosteroids (ICS) alone, are treated with a low, and if required, a medium or high dose of ICS combined with a long-acting β2-adrenoceptor agonist (LABA), plus as-needed reliever therapy with a short-acting β2-adrenoceptor agonist (SABA). In patients not achieving target control on ICS plus LABA therapy, such as budesonide/formoterol or salmeterol/fluticasone propionate single inhaler therapy, a third controller, such as leukotriene receptor antagonist (LTRA or theophylline), should be considered as a further stepwise addition in therapy .Budesonide is a potent corticosteroid that has acute effects on inflammation  and airwA total of six double-blind comparative clinical trials have consistently shown that the use of the combination of budesonide/formoterol with a fixed maintenance dose plus as-needed reliever therapy improved asthma control in adults and adolescents by reducing exacerbations, improving lung function and symptom control with a similar safety profile to higher doses of ICS alone ,8 or simAlthough SMART strategy has proved its efficacy and safety in controlled studies and has also recently been included in the GINA guidelines as a valid option for both maintenance and reliever therapy , data shThis was a randomised, open-label, parallel-group, multicentre study. An open randomised design was necessary as an important part of the Budesonide/formoterol (SMART) concept is the use of only one inhaler. The complexity of treatment options in the CBP arm with multiple controller therapies allowed  also excluded the possibility of blinding the comparator treatment arm. The study consisted of a 2-week run-in period followed by a 26-week randomised treatment period.The primary objective of the study was to compare the efficacy of Budesonide/formoterol (SMART) with treatment according to CBP in adolescent and adult patients with persistent asthma. The secondary objective was to collect safety data for treatment in the two treatment groups by evaluating the incidence and types of serious adverse events (SAEs) and discontinuations because of adverse events (AEs). In addition, we compared the cost of asthma medication between the budesonide/formoterol (SMART) group and the CBP group. For this purpose, a randomised, open-label, parallel-group design was selected at 194 centres in Belgium and Luxembourg under the supervision of 305 investigators, 44 of whom were specialists and 261 general practitioners. The trial was carried out between December 2004 and June 2006.The inclusion/exclusion criteria were designed to select patients who presented with symptoms while on treatment with ICS, or who where symptomatic or asymptomatic on ICS and LABA therapy with or without additional controller therapy, e.g. LTRAs. The study population was therefore intended to be consistent with the use of Budesonide/formoterol (SMART) as an alternative to high dose ICS, although combination therapy was allowed in the CBP arm.We enrolled out-patients of either gender aged ≥ 12 years who had been diagnosed with asthma > 3 months and who were prescribed ICS at a dose of ≥ 500 μg/day beclomethasone diproprionate (BDP) equivalent ± any other controller therapies, e.g. LABAs, LTRAs. To be eligible patients using ICS, monotherapy also needed to use ≥ 3 inhalations of as-needed medication for symptom relief during the last 7 days before enrolment. We excluded patients if they had used oral glucocorticosteroids (GCS) or if they had experienced an asthma exacerbation requiring a change in asthma treatment during the preceding 14 days . ParticiPatients started a 26-week study period receiving either SMART [budesonide/formoterol™ Turbuhaler™ ] , twice daily as maintenance plus as needed in response to symptoms or CBP treatment. All investigators were encouraged to provide CBP treatment according to GINA guidelines with treatment changes allowed  in response to increasing/decreasing symptoms or deteriorating/improving lung function in the CBP group. During treatment, visits were scheduled after 4, 13 and 26 weeks of study. Additional unscheduled visits at the initiative of physician and/or patient were allowed.During the treatment period, SMART-treated patients were not to use more than 10 inhalations as-needed during any single day in addition to their maintenance treatment. In the unlikely event, the patient needed more as-needed medication on a single day; the investigator was to be contacted for reassessment of the patient’s condition. Patients were instructed to rinse the mouth after intake of maintenance medication (morning and evening) during the treatment period, but not after intake of as-needed medication. During the treatment period, asthma medication other than budesonide/formoterol (SMART) was only allowed for the treatment of exacerbations.Any asthma medication including ICS and excluding SMART and/or maintenance oral steroids was considered as conventional best practice. Treatments were individually prescribed at the discretion of the investigator and within approved label for each product. During the treatment period, the CBP patient received the same instructions related to as-needed SABA medication as specified in the SMART group and as per normal practice, and patients were instructed to rinse the mouth after intake of any ICS-containing medication.The data collection process was designed to influence the patient and the physician behaviour as little as possible during the study course to maintain a real-life approach.The primary outcome was the time to first severe asthma exacerbation defined as deterioration in asthma leading to at least hospitalisation/emergency room  or oral GCS treatment for at least 3 days.Secondary outcome variables included the number of severe asthma exacerbations, the mean use of as-needed medication (reliever medication) and prescribed asthma medications. Patients completed their daily use of as-needed medication  in a notebook during the last 14 days before each visit during the treatment period. The patients were also instructed to document any changes in prescribed asthma medication during the study period on an ongoing basis.1) measurements was performed in addition. At both visits, PEF and FEV1 measurements were performed according to standard procedures before and after administration of two inhalations of bronchodilator . The highest PEF and FEV1 value out of three attempts was recorded.To assess lung function, pre and postbronchodilator peak expiratory flow (PEF) measurements were performed with a Mini Wright™ peak flow meter  in the GP clinic at baseline and at 6-month. For patients enrolled by a lung specialist, Forced Expiratory Volume in 1-s   and the The overall score for the ACQ5 was the mean of the five responses. At least four out of the five questions must have been answered to provide a value. The change from baseline to the average during the treatment period  was calculated for the ACQ5 score.The SATQ was used to measure the patient’s satisfaction with their inhaled asthma medication. The SATQ has been validated for use from the age of 18. The questionnaire includes 26 questions that are divided into four domains: effectiveness (eight questions), ease of use (seven questions), burden of asthma medication (six questions) and side effects and worries (five questions). The response options for each question are assessed on a seven-point scale. Negatively phrased items are reversed, so that a higher score indicates higher satisfaction with inhaled asthma treatment. The SATQ was administered only at baseline and at 6-month. Patients were reminded that they were scoring satisfaction with their inhaled asthma treatment and not satisfaction with other medical treatment or with the health care system.The cost of asthma medication used over the entire study period was estimated for each patient, based on information provided in the patient notebook. The Belgian Centre of Pharmacotherapeutic IBIP website was used to calculate the minimum number of units of each medication which would have been needed to be purchased, based on product name and duration of use. Mean (with standard deviation) and median costs per patient in each treatment group were then determined.To evaluate safety of treatment in both groups, the number and percentage of patients with SAEs and discontinuation of study treatment because of AEs were analysed. Any indications in the notebook of SAEs and/or discontinuations because of AEs needed to be discussed by the investigator with the patient.A sample size of 500 patients per treatment group  was required to detect a difference between the two treatment groups with 80% probability using a Log-rank test, under the assumption that, at the end of the study, 11% of the patients would have experienced a severe asthma exacerbation in one treatment group and 6% of the patients would have experienced a severe asthma exacerbation in the other treatment group.1 and cost of asthma medication were all compared between treatments using separate analysis of variance models, with treatment as factor and the baseline visit value as a covariate. Safety data were analysed by means of descriptive statistics. A p-value < 0.05 was considered as statistically significant.Time to first severe asthma exacerbation was described using Kaplan–Meier curves with treatments compared using a Cox proportional hazards model with treatment as a factor. The mean number of severe asthma exacerbations per patient was compared between treatments using a Poisson regression model with treatment as factors and the time in study as an offset variable. The confidence limits and the p-value were adjusted for over dispersion. The overall ACQ5 score, overall SATQ score, use of as-needed medication, PEF, FEVA total of 942 subjects were enrolled in the study and 908 subjects were randomised to either the Budesonide/formoterol SMART group or the CPB group. Overall, 867 subjects (95.5%) completed the study. The most common reason for discontinuation was the failure to meet eligibility criteria.All patients were included in the analysis of safety and efficacy.The demographics and key baseline characteristics of study subjects are summarised in The time to first severe asthma exacerbation for each group is plotted in The majority of patients in both groups had at least 1 day during which one or more as-needed inhalation was required (264 out of 450 patients in the Budesonide/formoterol SMART group and 291 out of 458 patients in the CBP group). Three patients in the SMART group compared with nine patients in the CBP group had at least 1 day with more than 10 as-needed inhalations.Overall, mean daily as-needed inhalation use remained about the same in both treatment groups, and there was no statistically significant difference between groups in terms of the average number of inhalations per day and as-needed free days .1 measurements were also performed at these time points.Pre- and post-BD PEF measurements were performed at Visit 2 and Visit 5. For patients enrolled by a lung specialist, pre- and post-BD FEV1 values (p = 0.33) (Mean PEF pre-BD increased from baseline for the subjects in the SMART group by 13.23 l/min and for the subjects in the CBP group by 10.84 l/min. The mean PEF post-BD (l/min) increased from baseline for the subjects in the SMART group by 9.17 l/min and by 7.19 l/min for subjects in the CBP group. There were no statistically significant differences between the two treatment groups for the mean pre-BD (p = 0.56) and post-BD PEF (p = 0.60) values or for the pre-BD (p = 0.48) and post-BD FEV = 0.33) .Asthma control assessed by questionnaire improved in both groups from baseline. In the Budesonide/formoterol SMART group, the mean ACQ5 score, which assessed symptom control and activity limitation during the treatment period, decreased by −0.30 compared with −0.17 in the CBP group (p < 0.01) , Table 32-agonist in combination with ICS in a single inhaler . In addition, 7% of patients (n = 34) used a separate long-acting β2-agonist and 27% of patients (n = 125) used an LTRA as an additional controller  group vs. the CBP group .Estimated drug cost used for asthma during the treatment period were analysed for the two treatment groups. Mean asthma drug cost/patient/month were 51.28 € for the patients in the Budesonide/formoterol SMART group and 66.54 € for patients receiving CBP .Drug costs linked to the use of asthma medication were significantly lower  for Budesonide/formoterol SMART group compared with the CBP group .In this study, no clinically important differences between the two treatment groups were observed with regard to the overall pattern of reported SAEs and withdrawal because of AEs. Both Budesonide/formoterol SMART and CBP regimens were well tolerated and no new or unexpected safety concerns were identified. A total of 23 SAEs were reported during treatment, 11 in the Budesonide/formoterol SMART group and 12 in the CBP group. Two patients in the Budesonide/formoterol SMART group died during the course of the study, one by suicide, the other following myocardial infarction. None of the reported SAEs was considered to be related to treatment by the investigator.Adverse events led to discontinuation in two patients (0.4%) in the SMART group and twp patients (0.4%) in the CBP group. Only one subject discontinued for a treatment-related event (sore throat in a patient in the CBP group).The study conducted in Belgium and Luxembourg confirmed that Budesonide/formoterol SMART  is an effective therapy for asthma control compared with physicians’ choice of CBP in a real-life setting.Study procedures were aimed to minimally influence patient’s behaviour and the pattern of the contacts with their physician. Given the complexity of treatment options in the conventional best practice arm, an open-label study design was chosen. This allowed the effectiveness of the single inhaler regimen without a separate as-needed inhaler, to be investigated without the need for separate reliever therapy as used in all previous double-blind studies. In the conventional best practice arm changes of the maintenance dose and other treatment, changes were permitted following any scheduled or unscheduled contact with the physician, but the same low maintenance dose of Budesonide/formoterol was used throughout in the SMART arm, this was not associated with any evidence of deteriorated asthma control or raised exacerbation and use of reliever therapy.The incidence and severity of severe asthma exacerbations were similar for the two treatment arms, but the overall incidence was far lower than assumed when powering the study. However, the total number of reported severe asthma exacerbations  and the total number of days of severe asthma exacerbation  tended to be lower in the Budesonide/formoterol SMART group compared with the CBP group.2-agonist (86%) in a single inhaler with 7% also using LABA via separate inhaler as maintenance or reliever therapy. In addition, 27% of patients in the CBP arm used LTRAs such that approximately 20% of patients used of at least three controller medications. Mean as-needed inhalation was similar in both treatment groups. However, the Budesonide/formoterol SMART group had lower overall inhaled corticosteroid load. The daily ICS dose was reduced significantly in the Budesonide/formoterol SMART arm vs. the CBP arm by around 300 mcg/day . Furthermore days with the use of oral corticosteroids to treat severe exacerbations were also reduced by 46% in the Budesonide/formoterol SMART group compared with the CBP group.In a previous open study comparing Budesonide/formoterol SMART with titration of maintenance treatment using salmeterol/fluticasone propionate , BudesonThe patient’s perception of asthma control, weekly symptoms and activity limitation assessed by a validated asthma control questionnaire (ACQ5) was improved to a greater extent over the study period with Budesonide/formoterol SMART than with CBP, although the two groups of patients were equally satisfied with their treatment at the end of the study. Of note is the fact that more than 95% of the patients did not change the maintenance treatment in the CBP group despite the fact that ACQ5 was > 0.75 for most of the patients. However this trial was undertaken 1 year before the publication of the GINA that recommended the use of ACQ in clinical practice to assess asthma control and adjust the treatment accordingly. That might explain the relative passivity of the doctors in adjusting the dose of maintenance treatment based on ACQ value.post hoc analysis also showed that drug costs linked to asthma medication used over the entire study period were significantly lower by approximately 25% for the Budesonide/formoterol SMART group. This is only relevant if we actually calculate the direct healthcare cost and not the drug cost alone. In this study, costs linked to hospitalisation were very low because of a few numbers of exacerbations. However, as hospitalisation days were lower in SMART group than in CBP group, taking into account this parameter would even strengthen the cost difference between the two strategies. This cost-effectiveness of the SMART strategy in Belgium/Luxembourg is keeping with the results of a larger study conducted according to a double-blind design  in maintaining or improving asthma control and reducing exacerbations. Budesonide/formoterol SMART also reduced corticosteroid use, the need for multiple controller therapies and treatment costs.


Sir,Cataract surgery requires adequate mydriasis which is achieved by topical administration or by intracameral injection of mydriatic agents. Since perioperative pupillary constriction may increase the risk of complications, mydriasis has to be maintained during surgery.In practice, using topical mydriatics increase the waiting time for surgery. It is several folds longer than the surgical procedure time. Topically, administrated mydriatics increase the risk of cardiovascular side effects due to their significant systemic absorption. These effects are particularly perilous in high-risk groups such as patients with hypertension or cardiovascular diseases.2Intracameral mydriatics are a rapid, effective, and safe alternative to topical mydriatics and can simplify preoperative routines. This regimen may reduce the risk for cardiovascular side effect. However,We evaluated the systemic effects of intracameral epinephrine in medically treated arterial hypertensive patients. The epinephrine is introduced after corneal incision.2-test, and a P < 0.05 was considered significant.The statistical significance was estimated using χThe study group comprised of 300 cataracts patients, medically treated for hypertension, and scheduled for phacoemulsification. Two or three drops of 1 mL of epinephrine (1 mg/mL) diluted in 1 mL of normal saline was injected into the anterior chamber in all patients. One drop (50 μL) contained 25 μg of epinephrine. Topical mydriatics were not used. All procedures were performed by one surgeon. No epinephrine was added to the irrigating solution.Peribulbar anesthesia using lidocaine 2% was achieved in all patients. Cataract surgery consists of a 3.2-mm superior clear corneal tunnel incision, intracameral injection of epinephrine, injection of viscoelastic material, capsulorhexis, hydrodissection, in the bag phacoemulsification, cortex aspiration, and insertion of foldable intraocular lens (IOL) in the capsular bag. The corneal incision was closed by hydration. A good mydriasis was maintained during surgery.Preoperative, intraoperative, and postoperative pulse rate and blood pressure were recorded.P = 0.07).The mean of preoperative blood pressure was 117 ± 3/75 ± 2 mmHg. The pressure increased significantly after injection of local anesthesia. At the beginning of surgery, blood pressure values dropped down to preoperative values. Intraoperative and postoperative blood pressure after intracameral injection of epinephrine remained constant: 117 ± 2.5/65 ± 1.5 mmHg. No significant pulse rate changes were noted in the patients. There was no significant difference in the circulatory parameters before and after intracameral mydriatic injection. (Any cataract surgery practice requires sufficient mydriasis which is habitually achieved by topical mydriatic or by intracameral injection of mydriatics agents.Previous studies have concluded that intracameral mydriatic are an efficient substitute to traditional topical mydriatics with time saving and easier technique.3 SystemiTo the best of our knowledge, this is the first study on the effect of intracameral injection of epinephrine on the blood pressure and pulse rate, in patients medically treated for arterial hypertension undergoing phacoemulsification.In our study, the intraoperative blood pressure and pulse rate remained stable. We conclude that intracameral epinephrine is a safe alternative to topical mydriatics in phacoemulsification. The use of epinephrine in intracameral injection can simplify the preoperative routine.


SCF (stem cell factor) is a pleiotropic cytokine exerting its role at different stages of bone marrow development and affecting eosinophil activation, mast cells and basophil chemotaxis and survival. The aim of the study was to assess concentration of SCF and its soluble receptor c-kit (sc-kit) in peripheral blood of patients with asthma referring it to asthma severity and phenotype.The study involved 107 patients with bronchial asthma, well characterized with respect to severity and 21 healthy controls. Concentration of SCF and sc-kit in the patients serum were measured by ELISA method.Mean serum SCF level in the group of asthmatics (n = 88) was significantly higher as compared to healthy controls . The level of SCF was higher in patients with severe asthma as compared to patients with non-severe asthma  and correlated with dose of inhaled glucocorticosteroids taken by the patients to achieve asthma control . The mean sc-kit serum level did not differ between asthmatic patients and healthy controls, however the level of sc-kit in non-severe asthmatics was significantly higher as compared to patients with severe asthma and healthy controls. In asthmatic patients (n = 63) the level of sc-kit correlated positively with FEV1% predicted value  and MEF25% predicted value . The level of sc-kit inversely correlated with the dose of inhaled glucocorticosteroids taken by the patients .Serum levels of SCF and its soluble receptor c-kit seem to be reflect asthma severity suggesting a role for these molecules in asthmatic inflammation. Hemopoietic cytokines play a crucial role in the activation and survival of cells involved in asthmatic inflammation. Stem cell factor (SCF)- the c-kit ligand, although initially was described as a mast cell growth factor  appearedAs mast cells and eosinophils are key cells in the inflammatory process ongoing in the airways of patients with asthma the role of SCF in this disease has been studied. The expression of mRNA for SCF and its receptor c-kit were shown to be higher in the bronchi of patients with asthma as compared to controls  and seruAs SCF is the cytokine acting mainly in the bone marrow, we argue if the airway inflammation typical for asthma may lead to increase of the level of circulating SCF. So the aim of the study was to assess if the concentration of SCF and its soluble receptor c-kit in peripheral blood is increased in patients with asthma and if it correlates with disease severity and asthma phenotype.The study involved 107 patients with asthma and 21 controls. SCF was assessed in 88 patients with asthma: 56 patients with severe and 32 patients with non-severe asthma, and the soluble c-kit level was assessed in 63 asthmatics: 41 severe and 22 non-severe  and the control group for c-kit consisted of 15 healthy subjects  recruited from the healthy Lodz inhabitants. Both SCF and sc-kit were assessed in 44 patients and in 15 control subjects.Asthma was diagnosed based on history, clinical examination and spirometric evaluation according to GINA definition. Severe refractory asthma was diagnosed according to ATS Workshop criteria which included use of oral glucocorticosteroids, high dose of inhaled glucocorticosteroids, daily use of a controller drug or short-acting beta 2 agonists, low respiratory function and history of exacerbation . In all Spirometry was carried according to ATS standards. Respiratory function (flow-volume curve) was measured with automatic spirometer  in patients who were without short acting beta 2 agonists for at least 8 h and long acting beta 2 agonists for at least 12 hours.Blood (5 ml for serum) was collected by venipuncture, serum was separated and frozen in -20°C. The concentrations of SCF and sc-kit SCF in serum were measured by ELISA method .Pharmacia Diagnostic, Sweden). Blood eosinophila  was assessed after staining with Pappenheim's method.The level of ECP and total IgE were measured by immunoenzymatic method . Total IgE and Eosinophil Cationic Protein(ECP) were measured in serum with ImmunoCAP  was carried out. P < 0,05 was considered statistically significant. Pearson correlation coefficient was used to compare level of SCF and sc-kit with FEV1% of predicted value, MEF% of predicted value and dose of inhaled glucocorticosteroids received by the patients.Mean serum SCF level in asthmatics (n = 88) was significantly higher as compared to healthy controls . The level of SCF was higher in the group of patients with severe asthma as compared to patients with non-severe asthma   and patients not treated with oral gluccocorticosteroids  were analyzed, the SCF level was significantly higher in both groups  as compared to mild asthmatics  and healthy controls   SCF level correlated with the dose of inhaled GCS taken by the patients to achieve asthma control  Fig . SCF levThe mean serum level of sc-kit in asthmatics without regard to asthma severity (n = 63) was similar to healthy controls p > 0,05). In patients with non-severe asthma the mean sc-kit level  was higher as compared to patients with severe asthma  and to healthy controls . There was no difference between mean sc-kit level in patients with severe asthma and healthy controls  the level of sc-kit correlated positively with FEV1% of predicted value   Fig . Sc-kit There was no correlation between serum SCF and sc-kit levels in patients with asthma, control subjects and in combined group .In this study we showed that serum level of SCF is higher in patients with asthma as compared to healthy subjects and is further increased in patients with severe refractory asthma. In parallel patients with severe asthma had decreased level of serum soluble c-kit as compared to non-severe asthmatics. Despite differences between SCF levels in patients with severe and non severe asthma serum SCF did not correlate with markers of asthma severity such as FEV1% and MEF% of predicted value, however it correlated with dose of inhaled corticosteroids needed to achieve asthma control.Previous studies showed increased production of SCF in different allergic disease like asthma, allergic rhinitis and atopic dermatitis -8. ExpreAlthough the serum level of SCF in healthy controls and patients with non- severe asthma was similar, the most severe patients had significantly higher serum SCF concentration in comparison both to healthy control and non-severe asthmatics. It is noticeable that despite aggressive anti-inflammatory treatment in the group of severe asthmatics  the level of SCF was significantly increased. It has been demonstrated that at the beginning of the treatment GCS can increase the level of SCF , howeverAs in asthmatic subjects not only SCF but also its receptor c-kit can be overexpressed on inflammatory cells we measured the soluble c-kit in the serum of patients . AlthougOur observations in line with study in patients with atopic dermatitis  which shWe were not able to correlate the level of SCF with aspirin hypersensitivity or concomitant nasal polyposis, although in previous study the increased expression of SCF within the nasal polyps of patients with asthma and aspirin hypersensitivity was reported . It suggOur study demonstrated that serum levels of SCF, a pleiotropic cytokine influencing development of two major cell lines in asthmatic inflammation- mast cells and eosinophils is elevated in patients with most severe asthma and may be important in pathogenesis of airway obstruction. Furthermore it seems that physiological down regulation of this cytokine by soluble kit receptor is also impaired in patients with severe asthma, thus modifying the SCF/c-kit interaction in asthmatics subjects.The authors declare that they have no competing interests.All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The treatment of hypertension in children and adolescents has been markedly changed in recent years by several factors, including the publication of new consensus recommendations, the obesity epidemic, and the increased availability of information on efficacy and safety of antihypertensive medications in the young. In this review we present an updated approach to the outpatient management of hypertension in the child or adolescent, utilizing representative cases to illustrate important principles as well as possible controversies. In adults, the definition of hypertension is based upon outcomes such as myocardial infarction and stroke; large-scale population studies have demonstrated that the incidence of these events increases in a linear fashion, beginning with blood pressures >120/80 mmHg  shou shou4] sIn the remainder of the article we have taken a case-based approach to the discussion of hypertension management. Instead of a straightforward discussion of lifestyle changes, medication choice, etc., we instead present three hypothetical patients that are similar to many children we have evaluated and treated for hypertension. We feel that this format lends itself to a more realistic discussion of key management issues that overlaps with other aspects such as diagnosis and prognosis.S. is a 14-year-old soccer player referred for evaluation of elevated blood pressure detected at a pre-sports participation screening at her school. Blood pressures obtained at the screening ranged from 137–149/75–80 mmHg. She is at the 50th percentile for height and weight and has no other chronic health problems or abnormal physical examination findings. Because of the elevated BPs, her soccer coach will not allow her to participate on the team. She and her family have asked you to write a letter allowing her to play without restrictions.Over 30 million children and adolescents in the USA participate in organized team sports . When thThe clinical history of the hypertensive athlete should include questions about the use of performance-enhancing substances, such as anabolic steroids, herbs, supplements, caffeine-containing energy drinks, and stimulants, as many of these can elevate blood pressure. The prevalence of anabolic steroid use among high-school athletes is as high as 3–7%, and approximately 10% of anabolic steroid users are teenagers , 7. FindThe current role of exercise stress testing in the evaluation of the hypertensive youth is not well defined. While exercise testing can be used to test the functional capacity for athletic activities, the American College of Sports Medicine does not recommend routine exercise testing of the hypertensive athlete –12. FurtProviders sometimes restrict hypertensive youth from athletics for fear that elevated BP values reached during exercise will lead to morbid events such as stroke or myocardial ischemia. The concern stems, in part, from the experience with vigorous exercise in hypertensive adults . Blood pHowever, the experience in hypertensive youth differs from that of adults. To date, sudden death due to exercise has not been reported in either overweight or hypertensive youth in the absence of other cardiovascular abnormalities, such as hypertrophic cardiomyopathy , 19. FurThe issue of sports participation in hypertensive children and adolescents has been considered by several expert panels, including the 36th Bethesda Conference, the NHBPEP Working Group, and the American Academy of Pediatrics Committee on Sports Medicine and Fitness. Competitive sports participation and highly static sports should be limited only in the presence of uncontrolled stage 2 hypertension or target-organ damage , 20. CarPhysicians are sometimes hesitant to allow hypertensive athletes to continue weight lifting. The concern comes from the extreme elevations in blood pressure (as high as 480/350 mmHg) and rare cases of subarachnoid hemorrhage reported in a small number of elite power lifters . HoweverTherapeutic lifestyle modification is essential for any child or adolescent with hypertension and should include regular physical activity, a diet limited in sodium but rich in fresh fruits and vegetables, fiber, and low-fat dairy products, and the avoidance of excess weight gain . RegularIn addition to the implementation of therapeutic lifestyle changes, some athletes will require pharmacologic therapy for hypertension management. The choice of medication should take into account side-effect profiles of particular importance to athletes . FurtherA. is a 6-year-old boy with autosomal dominant polycystic kidney disease. He was diagnosed at birth, due to the detection of bilateral flank masses on his initial physical examination in the newborns’ nursery. Recently, he has been noted to have intermittently elevated blood pressures during his follow-up visits to your office, with some readings as high as 130/78 mmHg. He has stage II CKD, with an estimated glomerular filtration rate (GFR) calculated by the Schwartz formula of 65 ml/min per 1.73 m2. Current medications include sodium bicarbonate, albuterol for asthma, and multivitamins.Children with CKD are frequently hypertensive. The 2006 annual report of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) showed that 39.3% of children enrolled in the chronic renal insufficiency registry were taking antihypertensive medications . The preCardiovascular disease is the most common cause of death in adults with CKD . The NatRecently, it has become apparent that children with CKD are also at increased cardiovascular risk. Analyses of the US Renal Data Systems database showed that children with end-stage renal disease (ESRD) have a 1,000 fold higher cardiac death rate than the age-matched general population, and cardiac death accounted for 38% of total deaths in children on dialysis , 33. MorThe NKF Work Group on Hypertension and Antihypertensive Agents in Chronic Kidney Disease defined the slowing of the progression of CKD as a principal goal of antihypertensive therapy in CKD . The ModWhile the above data are convincing, prospectively generated data are needed if we are to understand more clearly the role that hypertension plays in progression of CKD in children and adolescents. The previously mentioned CKiD study  includes2 body surface area and 80 ml/min per 1.73 m2 body surface area are randomly allocated to conventional or intensified blood pressure management with ramipril, aiming for the 50th to 95th percentile or below the 50th percentile, respectively, for 24 h mean arterial pressure [Many studies of adults with CKD demonstrate that antihypertensive regimens that include angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are more effective than regimens based on other classes of drugs in slowing progression of CKD, particularly in patients with proteinuria . Some ofpressure . Long-tepressure .Combination therapy with ACE inhibition and ARB may be more beneficial than either class of medication given alone, although previous studies have been limited by the use of submaximal dosing of both the combination ACE inhibitor–ARB and the comparison single drug , 41. Exp2 [Because fluid retention is a common cause of hypertension in CKD, diuretics are required in many patients to achieve target blood pressures. Thiazide diuretics are effective in lowering blood pressure and decrease cardiovascular risk in adults. Since thiazides are less effective at low levels of GFR, loop diuretics are preferred for patients with a GFR <30 ml/min per 1.73 m2 .Recently, the role of aldosterone antagonism has received significant attention in the treatment of hypertensive patients with CKD. Aldosterone receptor antagonists have been shown to have beneficial effects on cardiac fibrosis and may also further ameliorate proteinuria in CKD when used in combination with an ACE inhibitor or ARB . To dateStudies of adults with CKD show that both dihydropyridine calcium channel blockers  and non-dihydropyridine CCBs  are effective in lowering blood pressure. Non-dihydropyridine CCBs have the additional advantage of decreasing proteinuria and preserving renal function, whereas dihydropyridine CCBs do not have this effect, possibly because of a greater loss of renal autoregulation with dihydropyridines . When usThe NHBPEP Working Group recommended that children with chronic renal disease have a target blood pressure <90th percentile for age, gender, and height and that ACE inhibitors or ARBs should be used preferentially in children with proteinuric renal disease . A recenJ. is a 17-year-old girl referred by the obesity clinic for evaluation of elevated blood pressures. In addition to blood pressure readings of 135–147/70–82 mmHg, physical examination findings include height >95th percentile, body mass index (BMI) 47 kg/m2, acanthosis nigricans and striae on the proximal extremities and abdomen. Her regular exercise is limited to gymnastics class twice per week (30 min per session), and her diet includes many fast-food meals and at least four servings of soda daily. Her mother is also obese and has type 2 diabetes; her paternal grandfather died at age 50 years from a myocardial infarction. Laboratory evaluation reveals a fasting glucose concentration of 110 mg/dl, fasting insulin 50 μU/ml, total cholesterol 185 mg/dl, high-density lipoprotein (HDL) cholesterol 32 mg/dl, low-density lipoprotein (LDL) cholesterol 153 mg/dl and triglycerides 262 mg/dl.Obesity has reached epidemic proportions among children and adolescents in the USA , and itsWhile the pathogenesis of hypertension in the obese is complex and not fully understood, two hormonal abnormalities are likely involved: hyperinsulinemia, a consequence of peripheral insulin resistance , and hyperleptinemia, a consequence of the increased mass of adipose tissue. Hyperinsulinemia contributes to the development of hypertension by at least three proposed mechanisms: altered renal sodium handling, increased vascular resistance, and increased activity of the sympathetic nervous system (SNS) , 53. FurHypertension is a defining characteristic of the metabolic syndrome (MS), a constellation of abnormal clinical and laboratory findings, including central obesity, insulin resistance and dyslipidemia. The MS is associated with the development of atherosclerosis and is a strong independent predictor of cardiovascular events in hypertensive adults . At presBefore the patient proceeds to medications, however, lifestyle modifications should be implemented. Although success may be difficult to achieve, the benefits have been well documented in the literature. Two recent studies have demonstrated that short-term diet and exercise can result in weight loss, reduced blood pressure, and improvements in the abnormal laboratory findings associated with the MS in overweight children and adolescents , 60. FurPharmacologic management of hypertension in the MS has two unique aspects to consider: first, the cardiovascular effects of insulin-sensitizing medications, and second, the effects of some classes of antihypertensive agents on insulin sensitivity . MetformThe tendency of diuretics and beta-adrenergic blockers to affect glucose metabolism is well-known and needs to be considered when the physician is choosing an antihypertensive agent for obese children with signs of the MS . The comThe hypertensive child or adolescent with the MS also illustrates another important point in the therapy of hypertension, namely the need for other cardiovascular risk factors to monitor on an ongoing basis during treatment. Screening for dyslipidemia and impaired glucose tolerance should be performed on a regular basis, not only during the initial evaluation as recommended by the NHBPEP Working Group , but proThe most recent NHBPEP Working Group guidelines, published in 2004, provide comprehensive recommendations regarding the evaluation, diagnosis, and therapy of children and adolescents with elevated blood pressure [


Objective To examine the relation between blood pressure and the development of early retinopathy in adolescents with childhood onset type 1 diabetes.Design Prospective cohort study.Setting Diabetes Complications Assessment Service at the Children’s Hospital at Westmead, Sydney, Australia.Participants 1869 patients with type 1 diabetes  screened for retinopathy with baseline median age 13.4 (interquartile range 12.0-15.2) years, duration 4.9 (3.1-7.0) years, and albumin excretion rate of 4.4 (3.1-6.8) μg/min plus a subgroup of 1093 patients retinopathy-free at baseline and followed for a median 4.1 (2.4-6.6) years.Main outcome measures Early background retinopathy; blood pressure.Results Overall, retinopathy developed in 673 (36%) participants at any time point. In the retinopathy-free group, higher systolic blood pressure  and diastolic blood pressure  were predictors of retinopathy, after adjustment for albumin excretion rate , haemoglobin A1c , duration of diabetes , age , and height . In a subgroup of 1025 patients with albumin excretion rate below 7.5 μg/min, the cumulative risk of retinopathy at 10 years’ duration of diabetes was higher for those with systolic blood pressure on or above the 90th centile compared with those below the 90th centile . The risk was also higher for patients with diastolic blood pressure on or above the 90th centile compared with those below the 90th centile .Conclusions Both systolic and diastolic blood pressure are predictors of retinopathy and increase the probability of early retinopathy independently of incipient nephropathy in young patients with type 1 diabetes. Diabetic retinopathy affects most patients with type 1 diabetes after 15 years’ duration,7In addition to hyperglycaemia, hypertension has emerged as a risk factor for diabetic retinopathy and its progression in adults.13Retinopathy and nephropathy often coexist in patients with diabetes, so elevation of blood pressure may be due to nephropathy rather than essential hypertension. Normotensive patients with type 1 diabetes and nephropathy have worse retinal changes than hypertensive patients with normoalbuminuria,Adolescents with diabetes are an ideal group in which to study the effect of blood pressure on the very early development of retinopathy, because of the absence of coexistent disease, smoking, and treatment with other drugs in most patients. We hypothesised that blood pressure as a continuous variable is a predictor of early development of retinopathy and that this relation is present even in the absence of incipient nephropathy. Hence, we examined the association between systolic and diastolic blood pressure and the development of early retinopathy in a large cohort of adolescents with type 1 diabetes.This study included 1869 adolescents aged under 15  with a clinical diagnosis of type 1 diabetes who had retinal screening at the Diabetes Complications Assessment Service at the Children’s Hospital at Westmead  between 1989 and 2007. We excluded patients with secondary causes of diabetes . Participants in this study represent 45% of patients enrolled on the NSW type 1 diabetes registerWe screened adolescents for complications of diabetes according to established guidelines, which recommended annual assessment beginning five years after diagnosis  in patients with prepubertal onset of diabetes and two years after diagnosis in patients with pubertal onset.24We assessed retinopathy by fundal photography with a Topcon Fundus camera  after dilatation of the pupils with cyclopentolate 1% and phenylephrine 2.5%. We took non-simultaneous photographic pairs of seven standardised fields in each eye and then viewed them with a Donaldson Stereoviewer, which provided a three dimensional representation of the fundus and enabled microaneurysms to be more easily distinguished from haemorrhages and artefacts. From September 2004 we used the IMAGEnet 2000 Lite system to digitalise images. One experienced paediatric ophthalmologist (SH) graded the photographs according to the early treatment diabetic retinopathy study (ETDRS) adaptation of the modified Airlie House classification of diabetic retinopathy.26r=0.99). We defined microalbuminuria as albumin excretion rate ≥20 and <200 μg/min in two out of three samples. We defined normoalbuminuria as mean albumin excretion rate <7.5 μg/min in all urine samples.We determined albumin excretion rate from three consecutive timed overnight urine specimens. We used polyclonal radioimmunoassay  to measure urinary albumin from 1989 to March 2000. From April 2000, the laboratory changed to nephelometric assay using an IMMAGE analyser −0.501; 1c with high performance liquid chromatography . We converted glycated haemoglobin values to haemoglobin A1c . The interassay coefficients of variation were 1.1% and 1.2% for values of haemoglobin A1c of 5.95% and 9.76%.At each complications assessment, we assessed glycaemic control by measuring glycated haemoglobin colorimetrically2). We determined Z scores for body mass index by using age and sex related reference standards.29We used auscultation with a conventional mercury sphygmomanometer device and appropriate cuff sizes to measure systolic and diastolic blood pressure twice in the seated position after five minutes’ rest. We used the right arm for all measurements. We took the onset of the first and fifth Korotkoff phases as systolic and diastolic blood pressure. We report blood pressure measurements in mm Hg or in Z scores after adjustments for age and sex, as recommended in childhood and adolescence.2 test to compare groups for categorical variables. We evaluated differences between independent samples by using Student’s t test if variables were normally distributed or Mann-Whitney U test for skewed data.We present descriptive statistics as mean and standard deviation for normally distributed data or median and interquartile range when distributions were skewed. We used the χ1c, and BMI Z score or BMI >95th centile (used as definition for obesity in adolescents).We used Cox proportional hazards regression to examine predictors of the first retinopathy event in all participants (n=1869), with duration of diabetes as the time variable. Covariates included were systolic and diastolic blood pressure (mm Hg), sex, age, height (cm), haemoglobin ATo exclude the effect of early elevation of albumin excretion on the development of retinopathy, we used Kaplan-Meier survival curves to estimate the probability of developing the first retinopathy event in participants who had albumin excretion rate <7.5 μg/min (n=1025). We used high-normal cut off for systolic and diastolic blood pressure, defined as blood pressure on or above the 90th centile,1c, albumin excretion rate , height (cm), and Z score for body mass index as covariates. We examined clinically relevant interaction terms (as above), but they were not significant. To test for curvature, a quadratic blood pressure term was included in the analysis. We report significant results as odds ratio and 95% confidence interval.We did longitudinal analysis in participants who were retinopathy-free at baseline and followed prospectively by using generalised estimating equations so that correlations between repeated measures for a given patient could be taken into account.1c was 8.4% (7.7-9.3%) at first assessment. Overall, 673 (36%) participants developed retinopathy at any time during the follow-up. Moderate to severe non-proliferative retinopathy developed in 35 participants, and only one patient developed proliferative retinopathy during the study.For the whole group , median age was 13.4 years (interquartile range 12.0-15.2), duration of diabetes was 4.9 (3.1-7.0) years, albumin excretion rate was 4.4 (3.1-6.8) μg/min, and haemoglobin A1c were higher in patients who developed retinopathy.Table 1In all, 1231 (66%) participants had more than one visit, with median follow-up of 4.1 (3.1-7.2 ) years and a median number of visits of 3 (2-5). The incidence of retinopathy was 14.5 per 100 person years of follow-up. In this group, 138 participants had retinopathy at baseline, of whom 50 (36%) regressed, 56 (41%) were unchanged, and 32 (23%) progressed during follow-up.1c, age, and body mass index above 95th centile were significantly associated with a higher cumulative risk of retinopathy , systolic blood pressure, female sex, haemoglobin Av 35%, P=0.03)  , the cumulative risk of retinopathy at 10 years’ duration of diabetes was higher for those with systolic blood pressure on or above the 90th centile than for those below the 90th centile . Retinopathy was significantly associated with higher systolic and diastolic blood pressure. Age, duration of diabetes, haemoglobin A1c, predicted retinopathy  and higher diastolic blood pressure was associated with progression of retinopathy at 14 years.A potential weakness of the study is the use of auscultation without a random zero machine. However, the physicians taking the blood pressure were not aware of the retinal status of the patients.Our study has shown that higher diastolic blood pressure was still an independent predictor of retinopathy in adolescents with albumin excretion rate consistently below 7.5 μg/min, an earlier marker of incipient renal disease. Conversely, albumin excretion rate also predicted development of retinopathy in the entire cohort. Although antihypertensive agents prevent the progression from normoalbuminuria to microalbuminuria in patients with and without hypertension,Hypertension has been implicated in the development of diabetic retinopathy, on the basis of data from observational studies, which have not always controlled for other contributing factors. Interventional studies with angiotensin converting enzyme inhibitors have shown a reduction in progression of retinopathy in adults with type 1 diabetes,38The definition of hypertension is arbitrary. In adults with diabetes, lower targets for intervention have been recommended than in the general population,31This study shows that a continuous relation exists between blood pressure and risk of retinopathy. The clinical care of adolescents with type 1 diabetes is often shared between specialists and general practitioners. These findings highlight the importance of close blood pressure monitoring by all professionals involved in the management of adolescents with diabetes, regardless of urinary albumin excretion and glycaemic control, and indicate that lowering blood pressure, even in patients without hypertension or microalbuminuria, may improve retinal outcomes in diabetes. However, evidence for this proposal is lacking and interventional trials are needed to test the risks and benefits of lowering blood pressure in children and adolescents with type 1 diabetes.No longitudinal data exist on the effect of blood pressure on the development of retinopathy in children and adolescents with type 1 diabetesIn adults with diabetes, hypertension has emerged as a risk factor for diabetic retinopathy and its progressionHigher systolic and diastolic blood pressure contribute to the early development of diabetic retinopathy independent of glycaemic control, duration of diabetes, and albumin excretionBlood pressure had a continuous effect rather than a threshold effect on risk of retinopathy, suggesting that lower blood pressure protects the eye in diabetesThis relation has potential implications for blood pressure lowering treatment for the prevention of diabetic retinopathy in adolescents with type 1 diabetes


Pediatric sepsis is a commonly encountered global issue. Existing guidelines for sepsis seem to be applicable to the developed countries, and only few articles are published regarding application of these guidelines in the developing countries, especially in resource-limited countries such as India and Africa.An expert representative panel drawn from all over India, under aegis of Intensive Care Chapter of Indian Academy of Pediatrics (IAP) met to discuss and draw guidelines for clinical practice and feasibility of delivery of care in the early hours in pediatric patient with sepsis, keeping in view unique patient population and limited availability of equipment and resources. Discussion included issues such as sepsis definitions, rapid cardiopulmonary assessment, feasibility of early aggressive fluid therapy, inotropic support, corticosteriod therapy, early endotracheal intubation and use of positive end expiratory pressure/mechanical ventilation, initial empirical antibiotic therapy, glycemic control, and role of immunoglobulin, blood, and blood products.To achieve a reasonable evidence-based consensus on the basis of published literature and expert opinion to formulating clinical practice guidelines applicable to resource-limited countries such as India.Pediatric sepsis guidelines are presented in text and flow chart format keeping resource limitations in mind for countries such as India and Africa. Levels of evidence are indicated wherever applicable. It is anticipated that once the guidelines are used and outcomes data evaluated, further modifications will be necessary. It is planned to periodically review and revise these guidelines every 3–5 years as new body of evidence accumulates. Sepsis is a commonly encountered problem and a major cause of mortality in 80% of children worldwide.2 Till da3To identify levels of resource limitations and feasibility of interventions.To formulate guidelines with reference to consensus sepsis definitions, rapid cardiopulmonary assessment, and management of severe sepsis and shock.Several resource limitations were identified such as limited availability of pediatric intensive care unit (PICU) beds, in contr11Sepsis definitions: Definitions of sepsis based on International Consensus Conference 2005. Commonly used antibiotics include a third generation cephalosporin such as ceftriaxone and an aminoglycoside such as amikacin (Level 3).Source Control: Every patient presenting with severe sepsis should be evaluated for the presence of a focus of infection that is amenable to source control measures, e.g., drainage of an abscess, debridement of infected necrotic tissue, removal of a potentially infected device, etc.Hypoglycemia should be checked for and corrected (Level 2). Hyperglycemia should be avoided (Level 2).Hypoglycemia can have devastating neurological consequences and should be diagnosed early and treated immediately .Ionized hypocalcemia is common in neonates and children with sepsis admitted to PICU.32 AdminiMeticulous clinical monitoring for therapeutic endpoints without high technology facilities has shown a dramatic reduction in mortality in Vietnamese children presenting with moderate dengue shock syndrome and in I2 saturation, and CVP can be monitored at secondary level facilities. Use of cardiac monitor can give reliable continuous heart rate (HR) record. In absence of a monitor, HR could be determined by auscultation periodically; this may be done before, during, and after a fluid bolus has been administered.End-points such as OBlood Pressure: BP monitoring assists to regulate rate of fluid infusion, the need for vasoactive agents and further titration. In vasodilatory or warm shock, with wide pulse pressure narrowing of pulse pressure is an additional therapeutic goal.All the clinical end points may not be applicable in some patients.While normalization of heart rate is one of the most reliable signs of shock resolution, other causes of tachycardia may be fever, anxiety, pain, and SIRS. It may also be the only sign of ongoing seizure activity in a sedated, muscle-relaxed child. Anti-pyretic and analgesics, anti-seizure medications, source control and mother's close proximity can often help in achievement of normal range of heart rate in appropriate clinical scenarios. On the other hand heart rate, which falls within the normal range for age, in the presence of severe respiratory distress or impending respiratory failure and shock, is an ominous sign (of imminent cardiac arrest).Poor peripheral perfusion may be the result of cool environmental temperatures in very young infants. Recognition and resolution of shock in these young patients will depend on normalization of mental status, respiratory rates, and heart rates.There are concerns about the use of capillary refill and pulse volume, as there may be significant interobserver variability.Accurate urine output monitoring by catheterization in fluid unresponsive shock is useful, especially in settings without access to CVP monitoring.Time to achieve various therapeutic endpoints may be variable. There are no evidence-based guidelines for defining expected time frame of response for each of the monitoring parameters.2) is still beyond reach of most centers.Arterial blood gases (ABGs) and lactate estimations are available in a few centers; in others this cannot be used. Use of mixed venous oxygen saturations  route; Dopamine up to 10 μg/kg/min (Level 2).Obtain central venous access and airway if needed and feasible (Level 1).Following adequate intravascular volume repletion, continued presence of hypotension and/or poor perfusion (fluid refractory shock) warrants the consideration of vasoactive therapy, which should be goal directed.37The expert group agrees with the use of dopamine as the first-line vasopressor for fluid refractory hypotensive shock in the setting of low-systemic vascular resistance. Children with septic shock more often have myocardial dysfunction and low-cardiac output. Hence, it is preferable to combine inotropy with a vasopressor effect. Dopamine with or without dobutamine can be used as first-line drugs for giving this kind of support (Level 2). In children, the age-specific insensitivity to dopamine has to be kept in mind before starting dopamine particularly in infants <6 months.38Recognize dopamine resistant shock.Transfer to PICU.If possible, monitor CVP, echocardiography, mean arterial pressure (Level 2).Titrate fluids and vasoactive drugs to resolve shock based on CVP, echocardiography to achieve therapeutic goals.Reverse cold shock-resistant to dopamine  titrate central epinephrine (0.05–0.3 μg/kg/min)) (maximum dose 1 microgram/kg/min) (Level 2).(vi) Reverse warm shock with wide pulse pressure and/or low blood pressure by titrating central norepinephrine (Level 2).2/24 h) if child is at risk for absolute adrenal insufficiency (Level 2).(v) Begin hydrocortisone . A vasopressor such as norepinephrine is the drug of choice in such patients. It should be used only to restore adequate values of mean arterial pressure that is sufficient to restore urine output. The usual dose is 0.05–1.00 μg/kg/min.Children with septic shock more often have myocardial dysfunction with intense compensatory vasoconstriction. This leads to a state of low-cardiac output, with high-cardiac filling pressure and high-systemic vascular resistance, which clinically manifests as tachycardia, signs of hypoperfusion, prolonged capillary refill, cold extremities and low-to-low normal blood pressure and narrow pulse pressure (cold shock). An inotrope such as epinephrine is the drug of choice. The dose range is 0.05–1.00 μg/kg/min.The low-cardiac output state, characterized by persistent narrow pulse pressure and/or prolonged capillary refill even after use of dopamine may be improved with addition of dobutamine (up to 20 μg/kg/min) or low-dose epinephrine (<0.3 μg/kg/min) (Level 2B).At various stages of sepsis or the treatment thereof, a child may move from one hemodynamic state to another. Vasopressor or inotrope therapy should be used according to the clinical state.2/dose every 6 h until reversal of shock for pediatric sepsis patients with catecholamine-resistant shock and suspected or proven adrenal insufficiency (Level 2).[Corticosteroids should not be used routinely in all children with septic shock. The group recommends stress doses of hydrocortisone 50 mg/mLevel 2).40Up to this point most of the interventions can be performed in a peripheral setting to be followed as the guideline in resource-limited situation. Further management requires transfer of the patient to a PICU, reassessment of the patient's clinical status, arterial blood pressure, CVP, echocardiography and hemoglobin and packed cell volume (PCV). Generally, a low CVP will be an indication for more fluids, low blood pressure for more vasopressors, poor contractility of myocardium on echocardiography for titrating the dose of inotropes and low PCV, an indication for packed cell transfusion.At this stage, children in shock may be classified into two broad categories: warm shock and cold shock.Children with low BP. In these children, the dose of epinephrine should be titrated to achieve normal mean arterial pressure for age. Once this is achieved but the other goals of therapy are not yet achieved, one should consider adding a vasodilator such as nitroprusside and nitroglycerine, with very short half-life, or milrinone[Children in cold shock may be further categorized in two subgroups. (i) milrinone having bSecond category is that of children with normal BP. In these children, further action would depend on the pulse pressure. If the pulse pressure is low, milrinone would be the drug of choice (Level 1). However, if the pulse pressure is normal or high, norepinephrine and doubtamine should be titrated up.Vasopressin therapy may be considered as a last resort if patient has warm shock with low blood pressure unresponsive to norepinephrine.43 In pedAccurate dose delivery is an important component of vasoactive drug therapy. This can only be achieved with infusion pumps. When infusion pumps are not available, the infusions may be given using microinfusion sets whose drop size has been standardized. Mixing of more than one vasoactive drug in the same infusion set or infusion syringes is not recommended even when limited numbers of intravenous access ports are available. These drugs can be infused through the intraosseous route till the time that an intravenous access becomes available.A meticulous search for the causes of persistent catecholamine-resistant shock should be made if therapeutic goals are not achieved in spite of adequate volume loading and high doses of appropriate vasoactive agents. One must rule out mechanical causes of catecholamine-resistant shock such as tamponade because of pericardial effusion, pneumothorax, or increased intrabdominal pressure.Optimal hemoglobin for a critically ill child with severe sepsis is not known. A Canadian multicenter trial stronglyThe adult trial used a goal of 30% PCV (approx. 10 g/dL Hb) during the resuscitation phase of septic shock along with other interventions and showed a clear benefit. Hence, aThese recommendations may not apply to premature infants, children with severe hypoxemia, or cyanotic heart disease and to children who are actively bleeding.Correction of coagulation abnormalities does not improve outcome in all the patients and unneAlthough some pediatric studies have supported the use of intravenous immunoglobulins (IVIG) for severe sepsis,47 large Use of deep vein thrombosis (DVT) prophylaxis is recommended in postpubertal children with severe sepsis (Level 2).Therapy may be individualized. There are no graded recommendations.Continuous veno-venous hemofiltration may be clinically useful in children with anuria/severe oliguria and fluid overload. There are no graded recommendations due to lack of pediatric studies.The recommendations include use of rapid cardiopulmonary assessment and greater use of physical examination for achieving therapeutic endpoints. Early fluid resuscitation  based on weight with 40-60 mL/kg or higher may be needed.Early mechanical ventilation should be considered if hemodynamic instability continues beyond fluid therapy. Decreased cardiac output and increased systemic vascular resistance tend to be the most common hemodynamic profile. Dopamine with or without dobutamine is recommended as the initial agent for hemodynamic support. Use of dopamine by peripheral vein has been included in guidelines, as resource constrain may preclude use of central lines.There is enough evidence that early oxygen therapy, early aggressive fluid therapy to restore intravenous volume, and use of dopamine in fluid refractory shock have brought the mortality down. These interventions can be easily applied even in resource-limited circumstances even at primary and/or secondary level health facilities.Early appropriate antibiotics, correction of hypoglycemia, hypocalcemia, and avoiding hyperglycemia are recommended. Randomized controlled trials are needed to establish choice of inotropic and vasopressor therapy for initial management, dose, and timing of use of corticosteroids, administration of blood and blood products, protective mechanical ventilation, glycemic control, techniques of renal replacement therapy.Studies show that compliance with published guidelines tends to be inadequate. Further research evaluating individual components of guidelines and relative benefit of each of these interventions in resource-limited setting is needed, as also the benefit of adherence with guidelines and standardized set orders.


We investigated the effects on hemodynamics and gas exchange of a lipid emulsion enriched with omega-3 fatty acids in patients with ARDS.2/FiO2 ratio: 149 ± 40). Patients were randomized into 2 groups: Group A (n = 8) received the study emulsion Lipoplus® 20%, B.Braun Medical ; Group B (n = 8) received the control emulsion Intralipid® Fresenius Kabi (100% LCT). Lipid emulsions were administered during 12 h at a dose of 0.12 g/kg/h. Measurements of the main hemodynamic and gas exchange parameters were made at baseline (immediately before administration of the lipid emulsions), every hour during the lipid infusion, at the end of administration, and six hours after the end of administration lipid infusion.The design was a prospective, randomized, double-blind, parallel group study in our Intensive Medicine Department of Vall d'Hebron University Hospital (Barcelona-Spain). We studied 16 consecutive patients with ARDS and intolerance to enteral nutrition (14 men and 2 women; mean age: 58 ± 13 years; APACHE II score: 17.8 ± 2.3; Lung Injury Score: 3.1 ± 0.5; baseline PaONo statistically significant changes were observed in the different hemodynamic values analyzed. Likewise, the gas exchange parameters did not show statistically significant differences during the study. No adverse effect attributable to the lipid emulsions was seen in the patients analyzed.The lipid emulsion enriched with omega-3 fatty acids was safe and well tolerated in short-term administration to patients with ARDS. It did not cause any significant changes in hemodynamic and gas exchange parameters.ISRCTN63673813 The lipid emulsions generally used in the parenteral nutrition of critically ill patients are rich in long-chain triglycerides (LCT), especially linoleic acid . These preparations guarantee an optimal energy supply and prevent deficiency in essential fatty acids[The MCT/LCT emulsions are oxidized faster and provide fewer amounts of PUFAs than a LCT emulsions. While MCT emulsions do not interfere with eicosanoids synthesis, it has been considered as neutral. Thus MCT/LCT emulsions have been associated with a lower risk of lipid peroxidation and fewer alterations of membrane structures.2/FiO2 ratio, and a reduction in pulmonary inflammatory response, frequency of new organ failures, days of mechanical ventilation and long of stay in intensive care were observed[Polyunsaturated fatty acids of the n-3 series (PUFA n-3) are precursors of biologically active substances, e.g. the series 3 and 5 eicosanoids. These molecules use the same metabolic routes and compete for the same elongases and desaturases as linoleic and arachidonic, but ultimately they are mediators that have a much less active biological profile than linoleic acid derivatives. In 146  observed,8.Many patients with ARDS require sedoanalgesia and myorelaxation, inducing intestinal ileus and making intolerance to enteral nutrition. We hypothesized that adding n-3 to a MCT/LCT emulsion used in parenteral nutrition, should be beneficial because of the reduced amount of PUFA, would be less toxic than a lipid emulsion based on soybean oil, and that the addition of fish oil would be protective because of its anti-inflammatory properties. The pre2/FiO2 less than 200, and pulmonary capillary pressure less than 18 mm Hg[3), thrombocytopenia , severe renal insufficiency (creatinine > 6 mg/dl) or need for renal dialysis, signs of heart failure, transplantation, multiple blood transfusions, participation in other clinical trials simultaneously or in the last 60 days, treatment with nitrous oxide or corticoids , multiple organ failure, severe dyslipidemia, or propofol treatment.We studied 16 consecutive patients with ARDS in the first 48 hours of admission and intolerance of enteral nutrition defined by gastric aspirates higher than 300 ml. Patients were enrolled after approval of the study by the Committee of Clinical Trials of the Vall d'Hebron General University Hospital of Barcelona. All the patients or their representatives signed an informed consent before enrollment in the study. The inclusion criteria were: bilateral pulmonary infiltrates of sudden onset in the chest radiograph, PaO 18 mm Hg. Table 12), invasive blood pressure, pulmonary artery catheterization, and continuous cardiac output by thermodilution.Patients were sedated with morphine and midazolam and muscular relaxation was used as needed. All patients were ventilated mechanically . Monitorization included continuous electrocardiography (ECG), heart rate (HR), pulse oximetry (SpO2 transport (DO2), and pulmonary Qs/Qt were calculated with the usual formulas. Blood samples were drawn under anaerobic conditions through catheters placed in the radial artery and pulmonary artery. Oxygen (PaO2) and carbon dioxide (PaCO2) partial pressure, pH, and the concentration and mixed arterial and venous saturation of haemoglobin were measured using standard electrodes.A central venous catheter was inserted to administer the lipid emulsions. The basic parameters of pulmonary mechanics were monitored with the respirator and external monitoring. Cardiac output (CO) was measured by thermodilution. Systemic blood pressure (SBP), central venous pressure (CVP), pulmonary artery pressure (PAP), and pulmonary capillary pressure (PCP) were monitored by transducers placed on the middle anteroposterior chest, zeroed to atmospheric pressure, and calibrated electronically. Systemic (SVR) and pulmonary (PVR) vascular resistance, O® 20%, B.Braun Medical ; Group B (n = 8) received the control emulsion Intralipid® 20% Fresenius Kabi (100% LCT). The lipid emulsions were administered during 12 hours at a rate of 0.12 g/kg/h. During the lipid perfusion no recruitment maneuvres were done.In the first 48 hours after the diagnosis of ARDS and before receiving artificial nutrition, patients were randomized into two different groups: Group A (n = 8) received the study emulsion LipoplusMeasurements were made at baseline , six hours of perfusion (t 6); end of perfusion (t 12), and six hours after perfusion (t 18). Basic parameters of pulmonary mechanics, arterial and mixed venous gas analysis, hemodynamic parameters, and oxygen transport were measured at all stages.The data were imported from Access databases to SPSS. The following statistical parameters were calculated for numerical variables: mean and standard desviation. Differences in the means were analyzed by the T-test. Differences in time of the different parameters studied, depending on the type of emulsion, were assessed by repeated-measure analysis of variance (ANOVA). The level of statistical significance was defined as p < 0.05.At baseline, the groups were comparable table , 2 and 3After the administration of lipid emulsions, no significant modifications, intragroup or intergroup, in gas exchange or respiratory variables were observed table No significant differences were observed in either blood pressure or any other parameter studied during the administration of the lipid emulsions. Comparison of the changes between the two groups only yielded significant findings for pulmonary capillary pressure, which was lower at the end of emulsion infusion in group A, which received the lipid emulsion enriched with n-3 fatty acids. The fluid balance and medications used were similar in both groups table .The results of the present study suggest that none of the lipid emulsions administered at the rate and for the duration studied here produced gas exchange or hemodynamic disturbances in patients with ARDS. This suggests that the emulsions were clinically safe under these conditions. The changes in gas exchange induced by lipid emulsions in patients with ARDS depend on various factors such as the rate of administration and duration, composition of the lipid emulsions (as precursors of prostanoid synthesis), and the characteristics of the study populations tables , and 4b.2/FIO2, and an increase in MPAP, pulmonary vascular resistance and pulmonary venous admixture[2/FiO2 ratio and increased P(A-a)O2 and intrapulmonary shunting only in patients with ARDS[Analysis of the cardiopulmonary effects of lipid emulsions in our previous studies and the literature yields contradictory findings. In relation to the administration of LCT enriched emulsions; in healthy adults the administration of 4 hours infusion of Intralipid was followed by a significant increase in systolic and diastolic blood pressure as well as heart rate. 500 ml admixture. In diffwith ARDS. Slow inwith ARDS.2, MCT/LCT infusion produced an increase in oxygen consumption, cardiac output and CO2 production[Athough, theorically, the administration of emulsions enriched with MCT/LCT should have a neutral effect due to the few amount of PUFAs, the review of the literature was not concordant. In septic patients MCT/LCT administration did not induce any alterations in pulmonary hemodynamics, gas exchange, or distribution of ventilation/perfusion. No hemoroduction. In critroduction. A benefroduction. From thIt seems that soy bean lipid emulsions represent an imbalanced fatty acid supply, with an overabundance of n-6 PUFAs. Emulsions that include MCT and fish oil as a partial replacement for soy bean are now available, and evidence to data is that these emulsions offer some advantages over the use of soy bean alone. At the neutral metabolic effects of MCTs they added the beneficial properties of n-3 fatty acids, with diminished circulating concentrations of inflammatory eicosanoids -23. SeveIn our series of patients with ARDS, no significant changes were observed in hemodynamics or gas exchange, which demonstrated the safety of n-3 enriched lipid emulsions in these critical patients. The absence of theorically expected changes related to modifications observed in the eicosanoid profile may be due to the short duration of treatment with lipid infusion. However, now that it has been demonstrated that the n-3 enriched emulsion is safe, it can be used for studies in patients with ARDS who require PN. More prolonged use may reveal improvements in the clinical evolution of this group of patients, who traditionally bear a heavy morbidity and mortality.• Lipid n-3 enriched emulsions are safe in short term treatments with ARDS patients.• Despite theorical benefits in eicosanoid profile, the absence of clinical benefit could be due to the short treatment duration. Further studies are needed with longer infusion treatments.2: Pulse oximetry; CO: Cardiac output; SBP: Systemic blood pressure; CVP: Central venous pressure; PAP: Pulmonary artery pressure; PCP: Pulmonary capillary pressure; SVR: Systemic vascular resistance; PVR: Pulmonary vascular resistance; DO2: O2 transport; Qs/Qt: Venous admixture ratio; PaO2: Oxygen partial pressure in the artery; PaCO2: Carbon dioxide partial pressure in the artery; MPAP: Mean pulmonary artery pressure; P(A-a)O2: Alveolo-arterial gradient; PN: Parenteral nutrition; LIS: Lung Injury Score; APACHEII: Acute Physiology and Chronic Health Evaluation; PEEP: Positive End Expiratory Pressure.ARDS: Acute respiratory distress syndrome; MCT: Medium-chain triglycerides; LCT: Long-chain triglycerides; ω-3: Omega 3; PUFA n-6: Polyunsaturated series 6 fatty acid; n-3 fatty acids: Fatty acids of the n-3 series; PUFA n-3: Polyunsaturated fatty acids of the n-3 series; EPA 20:5 n-3: Eicosapentaenoic acid; DHA 22:5 n-3: Docosahexaenoic acid ECG: Electrocardiography; HR: Heart rate; SpOThe authors declare that this study has been financed by B. Braun Medical.JS participated in both the study design and coordination, and drafted the manuscript. JRM participated in both the study design and coordination, and performed the statistical analysis. JS participated in both the study design and coordination. PC participated in the study design. PS participated in the study design. MP designed and coordinated the study, and reviewed the final manuscript. All authors read and approved the final manuscript.