[Invasive pneumococcal pneumonia in children 0-24 months old: does bacterial resistance affect outcome]. / Neumonía neumocócica invasiva en niños de 0 a 24 meses: influye la resistencia bacteriana en la evolución?

INTRODUCTION: In Uruguay community acquired bacterial pneumonia is a significant cause of morbidity and mortality. S. pneumoniae is the most frequent agent. The disease is more severe in children less than two years old. The relationship between pneumococcal penicillin resistance and outcome is still an unresolved problem. OBJECTIVES: To compare the outcome of children 0 to 24 months old hospitalized in the Hospital Pediátrico-Centro Hospitalario Pereira Rossell, with invasive pneumococcal pneumonia caused by S. pneumoniae susceptible and resistant to penicillin. PATIENTS AND METHODS: Children 0 to 24 months old with invasive pneumococcal pneumonia, admitted between January 1st 1998 and December 31st 2005 were included. Susceptibility to penicillin was defined as a MIC < 0.06 microg/ml, reduced susceptibility was defined as a MIC of 0.1 to 1 microg/ml (intermediate) and as a MIC >or= 2 microg/ml (resistant). Outcome was evaluated with the following criteria: empyema, sepsis, septic shock, mechanical ventilation, and death. Length of hospital stay and outcome were compared in both groups. RESULTS: Inclusion criteria were met by 168 children. S. pneumoniae was susceptible to penicillin in 90 children and with reduced susceptibility in 78. Both groups were similar in age, comorbidity, nutritional status and initial antibiotic treatment. There were no significant differences in outcome and length of hospital stay. CONCLUSIONS: S. pneumoniae resistance to penicillin did not affect the outcome of pneumonia in this group of children.

Protein C antigen is not an acute phase reactant and is often high in ischemic heart disease and diabetes.

Protein C, an antithrombotic protein, was measured immunologically in 299 patients with clinical conditions associated with a high frequency of venous or arterial thromboembolism. The mean protein C antigen (PC:Ag) level was high for 48 patients with ischemic heart disease and, to a lesser extent, for 95 diabetics. In 28 patients with thrombotic strokes, 48 patients with proximal deep-vein thrombosis and in 80 patients with localized or metastatic tumors, mean PC:Ag was normal. Comparison of the pattern of changes of PC:Ag levels with those of fibrinogen, orosomucoid and prothrombin in 21 patients during the postoperative period and in 20 patients with active rheumatoid arthritis ruled out the possibility that high PC:Ag is non-specific, acute-phase reaction to inflammation, tissue injury or neoplastic growth. Therefore, high PC:Ag might be specifically related to the thrombotic tendency of these patients, but the mechanism of such a relationship remains to be clarified.

Pulmonary hypertension associated with long-standing thrombocytosis.

A case of thromboembolic pulmonary hypertension associated with long-standing thrombocytosis is presented. In this patient we found a significant local pulmonary platelet activation and thrombin generation as indicated by the existence of a transpulmonary gradient for thromboxane A2, beta thromboglobulin and fibrinopeptide A. Prolonged heparin and acetylsalicylic acid treatment resulted in improvement of clinical and hemodynamic conditions. These findings support the usefulness of anticoagulating and antiaggregating therapy in selected cases of pulmonary hypertension.

Prognostic value of baroreflex sensitivity assessed by phase IV of Valsalva manoeuvre in patients with mild-to-moderate heart failure.

BACKGROUND: In patients with heart failure, impairment of baroreflex function occurs early and contributes to sympathetic activation, however, at present its prognostic role has not been definitively established. AIMS: To evaluate the prognostic significance of baroceptor impairment in patients with different degrees of heart failure. METHODS: We enrolled 52 consecutive patients with heart failure, referred to our institution for functional evaluation. Twenty-eight suffered from ischemic cardiomyopathy and 26 from dilated cardiomyopathy. Thirteen patients were in NYHA class I, 20 in NYHA class II and 19 in class III. All patients underwent baroreflex assessment by phase IV Valsalva manoeuvre using Finapres finger monitoring of arterial blood pressure, echocardiography [with evaluation of left ventricular ejection fraction (LVEF), fractional shortening (LVFS), left ventricular end diastolic diameter (LVEDD) and mean pulmonary artery pressure] and functional evaluation by cardiopulmonary exercise test and 6-min walk corridor test within 2 days of hospital admission. RESULTS: Mean duration of follow-up was 26 months (range 6-35 months). At baseline, evaluation in 13 patients BRS was normal (>5 ms/mmHg), in 17 moderately impaired (1.5-5 ms/mmHg) and in 22 severely depressed (<1.5 ms/mmHg). Baroreflex function was relatively preserved in patients in NYHA class I (5.1+/-2.5) in comparison to patients in NYHA class II and III (2.1+/-2.3 and 2.08+/-1.9 ms/mmHg, respectively). Of the 52 patients who entered the study at the end of follow-up 15 died of cardiac cause and 5 underwent heart transplantation. Survival free from heart transplantation was 62% in patients with normal baroreflex function, 62% in patients with moderate impairment of baroreflex and 66% in patients with major derangement. NYHA class, LVEF, LVFS and LVEDD were significantly associated with event free survival while baroreflex function was not. CONCLUSIONS: Our results suggest that evaluation of BRS impairment by phase IV Valsalva manoeuvre has limited prognostic value in patients with heart failure.

Comparison of different methods of functional evaluation in patients with chronic heart failure.

BACKGROUND: Stratification of the severity of heart failure has major prognostic and therapeutic implications. AIMS: To prospectively compare different methods of assessment of functional capacity in patients with chronic heart failure (CHF). METHODS AND RESULTS: We studied 143 patients (78 male and 65 female) with CHF aged less than 70 years (mean 57.3 years). Functional assessment was made clinically according to NYHA classification and according to the Goldman Activity Scale Classification (GASC). Cardiovascular performance was measured by peak O(2) consumption (pVO(2)) and anaerobic threshold (AT) at cardiopulmonary exercise test and by the distance walked during a 6-min walk test (6-MWT). Clinical scales resulted significantly related. Peak VO(2) and AT showed a mild relation with distance covered at 6-MWT (r=0.56 and r=0.46, respectively). Concordance between NYHA classification and levels of performance at cardiopulmonary exercise test or at 6-MWT was less than 50%. CONCLUSION: Our results suggest that none of the usually employed methods give a definitive assessment of functional capacity of cardiovascular system and a high degree of discordance exists among the results of different tests in the same patient. Although NYHA classification maintains its value in clinical evaluation of patients with CHF, the 6-min walk test is recommended in patients with mild-to-moderate CHF (II-III NYHA classes) as a simple and useful screening test to select patients for further diagnostic evaluation.

Aspirin effect on early and late changes in acute lung injury in sheep.

OBJECTIVE: There have been several studies that have already explored the potential beneficial role of cyclo-oxygenase (CO) inhibitors on oleic acid (OA)-induced lung injury in different species. These studies report no significant effect of CO inhibition, though thromboxane B2 (TxB2) was effectively blocked. However, recent studies indicate that pre-treatment with aspirin (ASA) preserve gas exchange in OA lung injury in dogs. Aim of our study has been to evaluate the potential beneficial effects of the pre-treatment with low doses of ASA on gas exchange, hemodynamics, respiratory mechanics, prostanoids and lung histology in OA-induced lung injury in sheep. DESIGN: 0.09 ml/kg of OA was administered into the right atrium of 14 anaesthetized sheep. Six received a bolus of ASA (10 mg/kg i.v.) 30 min before OA, the others saline as placebo. MEASUREMENTS AND RESULTS: Pulmonary and tissue gas exchange, pulmonary and systematic hemodynamics, respiratory system mechanics, TxB2 and 6-keto-PGF1 alpha, leukocytes and platelets concentrations were measured throughout the subsequent 3 h and lung histology was effected at end-experiment. The principal findings of our study are: 1) ASA reduces OA-induced early pulmonary vasoconstriction and bronchoconstriction, parallelled by a suppression of TxB2 generation; 2) the late increase in pulmonary artery pressure and airway resistance due to OA is not inhibited by ASA; 3) the early disturbance in pulmonary gas exchange is reduced by ASA, whereas the late severe deterioration is exaggerated by ASA; 4) the stability of tissue exchange ratio (R) at approximately 1 in ASA-group compared to its fall to approximately 0.7 in controls. CONCLUSION: Our findings suggest that ASA: 1) is only effective to treat the very transient TxB2-induced pulmonary vasoconstriction resulting in hydrostatic edema, and it is ineffective, even accentuates, the subsequent major pulmonary endothelial cell injury leading to alveolar flooding that is unrelated to TxB2; 2) has a transient protective effect on the TxB2-induced early bronchospasm; 3) has a biphasic behaviour on gas exchange, with a benefit which lasts only one hour and then results in a worse gas exchange; 4) has an immediate, stabilizing, persisting effect on R, contrasting with its transient effect on pulmonary hemodynamics and PaO2.

Effects of calcium channel blockers on platelet aggregation and thromboxane A2 formation: an in vivo double blind randomized study.

In this double blind cross over study against placebo the in vivo effects of diltiazem, nifedipine and verapamil on platelet aggregation and Thromboxane A2 (TxA2) formation were evaluated in eighteen healthy adults. No significant inhibition of platelet aggregation or TxA2 formation was found either after acute or short term (8 days) administration of the three calcium channel blockers at the usual therapeutical dosages. Our study indicate that diltiazem, nifedipine and verapamil are unable to significantly affect platelet aggregation and TxA2 formation in healthy subjects.

Increased protein C and fibrinopeptide A concentration in patients with angina.

Protein C and fibrinopeptide A (FpA) levels in plasma were measured in 30 controls and in two groups of patients with angina. The first group was formed by 27 patients suffering from spontaneous ischemic attacks (active angina). The second one was formed by patients who had previously suffered from angina, but were free from myocardial ischemic attacks for at least one month (inactive angina). Protein C (measured by electroimmunoassay) and FpA (radioimmunoassay) were higher than controls in both groups but were significantly higher in patients with active angina than in patients with inactive angina. A clear trend toward a linear correlation existed between protein C and FpA levels, though it did not reach the statistical significance. These results confirm a significant involvement of blood clotting system in ischemic heart disease and specially in active angina.

No changes in PAI-1 levels after four-month n-3 PUFA ethyl ester supplementation in healthy subjects.

Recent studies have indicated that diets rich in fish or supplemented with fish oils may increase PAI-1 plasma levels. However, this finding has not been consistent and could be related, at least in part, to the type of supplementation. Aim of this study was to investigate the effects of medium-term treatment with n-3 polyunsaturated fatty acid (PUFA) ethyl esters on fibrinolysis. Twenty normolipemic healthy male subjects (age 27 to 41 yrs) were randomly assigned to receive either 4 x 1 g capsules of n-3 PUFA ethyl esters (ESAPENT, Farmitalia-Carlo Erba, Milan, Italy) or 4 x 1 g capsules of olive oil (as placebo) for 4 months in a double blind study. Blood samples for lipid and hemostatic studies were obtained at 0, 2, and 4 months of treatment and 1, 2 and 3 months of wash-out. Plasma lipids, fibrinolytic system, lipoprotein (a)-Lp(a)-, fibrinogen (Fbg) and prothrombin activation fragment 1+2 (F1+2) were assayed. No changes in these parameters were observed in the group of ten subjects treated with olive oil. After n-3 PUFA supplementation no significant alterations were found in plasma lipids, even if a trend to lower triglyceride and Lp(a) levels was detectable. No changes in either PAI-1 activity or PAI-1 antigen levels or F1+2 plasma levels were observed. A trend to lower Fbg levels was found after n-3 PUFA, but changes were not statistically significant. The results of this study indicate that a 4-month treatment with 4 g daily n-3 PUFA ethyl esters does not affect PAI-1 plasma levels.

The prominent role of thromboxane A2 formation on early pulmonary hypertension induced by oleic acid administration in sheep.

The early increase of pulmonary artery pressure observed in different models of experimentally induced lung injury have been shown to be associated with the release of vasoconstrictive agents by activated platelets. The aim of this study was to evaluate the pattern of these metabolites, in particular TxA2, and the effects of the inhibition of their production by ASA on the modifications of pulmonary hemodynamics induced by oleic acid administration in sheep. Group I (8 sheep) was infused with oleic acid (0.09 ml/kg at 0.02 ml/min) while in group II (6 sheep) ASA (10 mg/kg i.v.) was administered 30 minutes before oleic acid infusion. In group I pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) were significantly higher at the end of the infusion while cardiac output (CO) significantly decreased in comparison to baseline values. A marked increase in plasma TxB2 levels paralleled pulmonary hemodynamic changes. Also plasma 6 keto PGF levels increased after OA infusion. The early increase in PAP and PVR was significantly lower in group II (p less than 0.005) while CO did not undergo any significant change. ASA pretreatment significantly blunted the rise of TxB2 concentrations and prevented the elevation of 6 keto PGFa. These results indicate that early pulmonary hypertension in oleic acid induced injury is mainly related to TxA2 released from platelets and leukocytes and that pulmonary hemodynamic changes are significantly inhibited by ASA pretreatment.

The role of extraplatelet thromboxane A2 in unstable angina investigated with a dual thromboxane A2 inhibitor: importance of activated monocytes.

BACKGROUND: The role of thromboxane A2 (TxA2) in unstable angina has not yet been defined. TxA2 receptor antagonists may be of value in studying this role. METHODS: To investigate whether TxA2 has a pathogenetic effect on the occurrence of myocardial ischemia and from what source TxA2 originates, we studied TxA2 formation by unstimulated monocytes from patients with unstable angina (n = 40), stable effort angina (n = 20), and controls (n = 20). We also compared the effects of picotamide (1200 mg/day), a TxA2-synthase inhibitor and TxA2-receptor antagonist, with those of aspirin (325 mg/day) on myocardial ischemia and TxA2 formation by monocytes and platelets. The double-blind randomized study was performed on patients with unstable angina on continuous Holter monitoring. RESULTS: In the presence of autologous lymphocytes, unstimulated monocytes from patients with unstable angina formed significantly (P < 0.001) more TxA2 than those from controls or from patients with effort angina. Although TxA2 formation by circulating monocytes and platelets was inhibited to a greater degree by aspirin than by picotamide (88 +/- 6 and 98 +/- 2%, respectively, versus 65 +/- 2 and 74 +/- 1%, P < 0.001), aspirin failed to affect the occurrence of myocardial ischemia whereas picotamide significantly (P < 0.001) reduced the number of anginal attacks (84.8%), silent ischemic episodes (64.2%), and overall duration of ischemia (69.8%), in comparison to the run-in period. CONCLUSIONS: These results indicate that TxA2 formed by monocytes contributes to the pathogenesis of myocardial ischemia in unstable angina. TxA2 formation occurs mainly in extravascular spaces, probably within the coronary vascular wall. Picotamide appears to control myocardial ischemia effectively in patients with unstable angina.

Biosolids application in the Chihuahuan desert: effects on runoff water quality.

Surface-applied biosolids, the option most often used on range-lands, can increase the concentration of macronutrients and trace elements in the runoff water and can potentially produce eutrophication or contamination of surface waters. In this study, the effects of postapplication age of biosolids (18, 12, 6, and 0.5 mo) and rate of application (0, 7, 18, 34, and 90 Mg ha(-1)) on the quality of runoff water from shrubland and grassland soils were assessed. Between July and October 1996 simulated rainfall was applied to 0.50-m2 plots for 30 min at a rate of 160 mm h(-1). All of the runoff water was collected. The concentration of NH4+ -N, NO3- -N, PO4(3-)-P, total dissolved phosphorus (TDP), Cu, and Mn in the runoff water increased with rate of biosolids application and decreased with time of postapplication on the two soils. The highest PO4(3-)-P and NH4+ -N concentrations, 4.96 and 97 mg L(-1), respectively, were recorded in the grassland soil treated with 90 Mg ha(-1) of biosolids 0.5 mo postapplication. For the same soil, rate, and postapplication age of biosolids, Cu exceeded the upper limit (0.50 mg L(-1) in drinking water for livestock. Ammonium N and PO4(3-)-P should be the main compounds considered when surface-applying biosolids. Ammonium N at concentrations found in all biosolids-treated plots may affect the quality of livestock drinking water by causing taste and smell problems. Orthophosphate can contribute to eutrophication if the runoff from biosolids-treated areas enter surface waters.

Doppler echocardiography in suspected lone atrial fibrillation.

Echocardiography is frequently required in patients with atrial fibrillation (AF) to exclude underlying heart disease. In the present investigation the authors evaluated 56 patients with paroxysmal AF (PAF) (27 men, 29 women, mean age 54+/-11.3 years) in whom lone AF was suspected on clinical grounds. M-mode, B-mode, and Doppler examination were performed and measurements taken according to American Society of Echocardiography criteria. Left atrial diameter, left and right atrial volumes, left ventricular (LV) diameters, LV fractional shortening, and Doppler indexes of LV diastolic function were not different in patients with PAF in comparison with those of a control group of 56 age-matched subjects free from cardiovascular diseases. Echocardiographic examination results were entirely normal in 32/56 patients (57%) vs 39/56 of the control group (69%). Mitral valve prolapse was found in five patients (9%), but only one showed mild mitral regurgitation. Doppler examination disclosed a mild (+/++) mitral regurgitation in eight patients and a small aortic or pulmonary diastolic flow in four and two patients, respectively, in the absence of significant morphologic valvular abnormalities. In these patients the sizes of heart chambers were entirely normal. Aneurysm of the interatrial septum was found in one patient and an increased thickness of the epipericardial junction in another two patients. Finally two patients had a small increase of right atrial volume without demonstrable causes. The results suggest that lone AF can be correctly suspected on the basis of clinical findings (history, physical examination, and ECG) and that in these patients echocardiography rarely discloses organic heart disease.

Decreased baroreflex sensitivity assessed from phase IV of Valsalva maneuver in mild congestive heart failure.

Decreased sensitivity of cardiopulmonary and arterial baroreceptors has been hypothesized to sustain sympathetic activation in patients with heart failure. In the present investigation the relationship between the impairment of baroreflex sensitivity and clinical severity of congestive heart failure was investigated. The authors studied 58 patients with heart failure (14 in NYHA class I, 22 in NYHA class II, and 22 in NYHA class III), 38 women and 20 men, age range 28-65 years. Thirty-two patients suffered from idiopathic dilated cardiomyopathy and 26 from coronary heart disease. As control group they examined 21 age-matched subjects. Baroreceptor sensitivity was studied by using the Valsalva maneuver as stimulus. Arterial pressure and heart rate were measured noninvasively by Finapres instrument (Ohmeda) and signals were recorded and elaborated with a personal computer. A decrease of baroreflex sensitivity was already demonstrable in NYHA class I patients (4.72 +/- 3.31 vs 9.25 +/- 5.05 msec/mm Hg in control group) (p < 0.005). A further impairment of baroreceptor response was found in patients in NYHA class II (1.94 +/- 2.88 msec/mm Hg, p < 0.001) and class III (1.78 +/- 1.52 msec/mm Hg, p < 0.001). Baroreceptor response showed a significant correlation with functional NYHA class (r = 0.61, p < 0.001) and anaerobic threshold (r = 0.57, p < 0.001) while the correlation was less tight with left ventricular end-diastolic diameter, fractional shortening, left ventricular ejection fraction, pulmonary mean arterial blood pressure, cardiac index, distance at 6 minutes walk corridor test, and maximal oxygen consumption (VO2max). These results suggest that baroreceptor function may be impaired early in the clinical course of heart failure and may contribute to sympathetic activation.

Left atrial size changes in patients with paroxysmal lone atrial fibrillation. An echocardiographic follow-up.

Left atrial enlargement has been demonstrated to occur as a consequence of the arrhythmia in patients with chronic atrial fibrillation (AF) in the absence of organic heart disease, whereas contrasting results have been reported in patients with paroxysmal lone AF. In the present investigation the behavior of left atrial size was followed up for an average period of 30.3 months in 20 patients with paroxysmal lone AF since their first arrhythmic episode. No significant changes in left atrial size were found at the end of the follow-up period. In 65% of patients the arrhythmia recurred at least once yearly. Left atrial size at enrollment was not significantly different in these patients from those without recurrences and did not change in either group during follow-up. The results suggest that in patients with lone AF left atrial dilatation occurs only after the arrhythmia becomes chronic. Early restoration of sinus rhythm may interrupt the vicious circle leading to atrial enlargement.

Treatment options for acute venous thromboembolism in the older patient.

The incidence of deep venous thrombosis and pulmonary embolism increases exponentially with age. This pattern reflects the age-related increase in the frequency of serious medical diseases that require prolonged bed rest and predispose to the activation of hemostatic processes. Treatment with heparin and thrombolytic agents is clearly effective in patients age 65 and older, even though an elevated susceptibility to hemorrhagic complications has been demonstrated. Careful evaluation of individual hemorrhagic risk, a slight decrease of doses, and careful laboratory monitoring may decrease the number of clinically significant bleedings without impairing therapeutic results. Low-molecular weight heparin may represent a major advance in the treatment of thromboembolic disease, but studies that specifically address its use in older patients are needed.

Predictors of successful at-home chemical cardioversion in new-onset atrial fibrillation.

Prehospital treatment of new-onset supraventricular arrhythmias can be attempted by physician-staffed mobile intensive care units to decrease the hospitalization rate and expense. Identification of patients suitable for at-home pharmacological treatment may help in the triage of patients with new-onset atrial fibrillation (AF). In the present investigation, the value of several clinical variables to predict the success of pharmacological at-home cardioversion was tested. A total of 924 patients with new onset (less than 24 h) AF, rescued by the Florence Mobile Coronary Care Unit (MCCU), were included in the study. By univariate analysis, female sex, palpitations as symptoms leading to MCCU call and a short delay between symptom onset and MCCU intervention were associated with a favourable outcome of treatment, whilst dyspnoea as the main complaint requiring MCCU intervention and the association of AF with an acute cardiovascular event (angina, acute myocardial infarction or pulmonary oedema) were negatively associated with the success rate of treatment. The cardioversion rate was not significantly different in patients with underlying heart disease or in patients with lone atrial fibrillation. By multivariate analysis, only sex and the drug employed for treatment (positive relation for propafenone and bunaftine, negative for amiodarone, digoxin and verapamil) were significant predictors of the outcome of MCCU intervention. Our results suggest that patients with new-onset (less than 24 h) AF with or without underlying heart disease whose main complaint is palpitation can be successfully cardioverted at home with a class IC drug (propafenone). Patients with acute coronary syndromes or left ventricular failure are good candidates for elective cardioversion after hospitalization.

Early out-of-hospital lidocaine administration decreases the incidence of primary ventricular fibrillation in acute myocardial infarction.

This study was designed to assess the effectiveness of early prehospital intravenous administration of lidocaine in preventing primary ventricular fibrillation (PVF) in patients with suspected acute myocardial infarction (AMI). Sixty patients with suspected AMI, seen by the Mobile Coronary Care Unit (MCCU) of Florence, were randomly allocated at home to treatment with lidocaine (bolus i.v. of 1 mg/kg, followed by an infusion of 4 mg/min) or placebo (infusion of saline at a rate of 1 mL/min), respectively. The lidocaine group (27 patients) and the control group (33 patients) were not significantly different in age, clinical condition, or time of randomization. The diagnosis of AMI was confirmed in all 60 patients during the hospital stay. Ventricular fibrillation (VF) occurred in 5 patients in the control group in comparison to none in the lidocaine group (P < 0.05). Three patients experienced VF at home and were successfully resuscitated by an MCCU cardiologist. In another two patients, VF occurred during the first 4 hours after onset of symptoms. No major side effects were observed after the infusion of lidocaine. Our findings support the effectiveness of the prophylactic administration of lidocaine in preventing PVF in the prehospital phase of AMI and suggest that the drug can be safely administered in this setting by prehospital personnel.

Evaluation of a mobile coronary care unit protocol in patients with acute onset chest pain.

This study was designed to assess the accuracy of a diagnostic protocol of the mobile coronary care unit (MCCU) of Florence for acute chest discomfort. During 1986, 706 patients with chest pain were seen by the MCCU. Of these, 324 of 376 (95.2%) of those hospitalized and 247 of 324 (76.2%) of the nonhospitalized patients were entered in the study. The MCCU diagnosis of acute myocardial infarction (AMI) was confirmed in 120 patients (80.3%). A false positive diagnosis of AMI was made in 27 patients (6.9%), while in 37 patients AMI was not diagnosed at the first MCCU clinical examination (false negative). The sensitivity in the diagnosis of AMI was 80.5%, the specificity 91.8%, and the diagnostic accuracy 89.1%. In the recognition of acute coronary syndromes (AMI + unstable angina), sensitivity and specificity were, respectively, 94.0% and 94.4%. The protocol of the Florence MCCU provides high accuracy in the diagnosis of AMI and acute coronary insufficiency; close adherence to the protocol can decrease the number and the costs of undue hospital admissions while protecting the safety of patients.