Universitatea Stefan cel Mare Facultatea de Inginerie Alimentara Ingineria Produselor Alimentare

Aditivi alimentari: Acid sorbic si Manitol

Profesor: Ropciuc S.

Student: Maritanu Anca Roxana An/ grupa: IV 1A

Antisepticele sunt substante chimice care opresc dezvoltarea si actiunea unor microorganisme (substante bacteriostatice) sau le pot distruge (substante bactericide), in functie de concentratia folosita si de specia microorganismelor (Satinover si Marinescu, 1962). Activitatea antisepticelor este dependent de concentratia substantei, durata de contact, temperature, specie, numarul de microorganisme si stadiul de dezvoltarea a microorganismelor, compozitia chimica a mediului si PHul acestuia. Concentratia: Pentru aceleasi conditii de mediu, aceeasi temperatura si acelasi numar de microorganism, actiunea antisepticului asupra microorganismelor creste odata cu concentratia sa in produsul de conservat, fiecare antiseptic caracterizandu-se printr-o anumita putere de distrugere sau doza letala. Durata de contact: Durata de contact este invers corelata cu concentratia antisepticului; cu cat concentratia antisepticului este mai mare cu atat durata de contact este mai redusa si invers. Temperatura: Eficacitatea unui antiseptic creste in progresie geometrica, in conditiile in care temperatura creste in proportie aritmetica, aceasta regula nefiind insa valabila pentru antiseptic volatile sau gazoase. Numarul initial de microorganisme: Cu cat gradul de contaminare initial este mai mare cu atat eficacitatea antisepticului este mai mica, respectiv pentru a realiza un efect bactericid normal trebuie marita doza de antiseptic. Specia de microorganisme: Comportarea la antiseptice este in functie de felul microorganismelor (drojdii, mucegaiuri, bacterii) precum si in functie de speciile si tulpinele respective. De exemplu, bacteriile gram-negative sunt mult mai rezistente la actiunea antisepticelor.
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Se considera ca diferentele de rezistenta ale microorganismelor s-ar datora deosebirilor ce exista intre ele in ceea ce priveste tensiunea superficiala, structura si compozitia chimica a celulei. Stadiul de dezvoltare: Eficacitatea antisepticelor este mai mare atunci cand microorganismele se afla in faza de lag, cel putin in cazul microflorei epifitei normale. Sporii, practic, nu sunt afectati de antisepticele utilizate in industria alimentara. Compozitia chimica: Alimentele prin compozitia lor chimica influenteaza actiunea antisepticului. De exemplu, alimentele cu un continut ridicat de proteine sunt mai greu de conservat cu antiseptice care elibereaza clor sau oxigen. Alimentele cu un continut ridicat de zaharuri reducatoare micsoreaza actiunea antiseptica a SO2 prin formarea de compusi de aditie cu gruparile aldehidice sau cetonice ale zaharurilor PH-ul mediului: In general, eficacitatea antisepticelor este cu atat mai mare cu cat PH-ul mediului este mai mic, adica mediul este mai acid. Principalele substante antiseptice utilizate in industria alimentara apartin la doua subgrupe: A antiseptice propriu zise: acidul sorbic, sorbatul de sodiu, sorbatul de potasiu, sorbatul de calciu, acidul benzoic, benzonatul de sodiu, benzonatul de potasiu, benzonatul de calciu, dioxidul de sulf, sulfitul de sodiu, bisulfitul de sodiu, etc. B - substante destinate in principal altor utilizari, dar care pot avea un efect conservant secundar: azotitul de potasiu, azotitul de sodiu, azotatul de sodiu, azotatul de potasiu, acid acetic, etc.

Acidul Sorbic (E 200) CH3CH=CHCH=CHCOOH

Denumirea sa chimica este acid 2,4-hexadienoic sau acid trans, trans-hexa-2,4-dienoic. Are formula chimica C6 H8O2, si are masa moleculara 112,12. Se gaseste in fructele de Sorbus Aucuparia L. Si in fructele altor rozaceae. Industrial este sintetizat prin reactia dintre aldehida crotonica si acid malonic in prezenta de piritina. Se mai poate obtine si prin condensarea aldehidei protonice cu cetena. Rezulta doi compusi: o -lactonina si un poliester care prin incalzire se descompun, cu formare de acid sorbic. Acidul sorbic este o substanta solida cristalizata de culoare alba cu un miros caracteristic slab, care nu prezintavariatii de culoare dupa 90 de minute de incalzire la 105C. Are punctul de topire de 133-135C si de fierbere de 228C (cu descompunere). Are o solubilitate redusa in apa rece (0,15-0,16g% la temperatura de 20C), dar mai crescuta in apa calda (0,6g% la 50C si 3,8g% la 100C). Acidul sorbic este antrenabil cu vapori de apa, se solubilizeaza mai usor in etanol (12,9g% la 20C). Are pKa = 4,8. Prezinta o activitate antimicrobiana care cuprinde un spectru larg de microorganisme. Activitata conservanta optima se realizeaza la PH = 4,5 (pana la PH = 6,5). Aditivul alimentar trebuie sa contina minimum 99% substanta activa (dupa uscare in vid timp de 4 ore intr-un desicator cu acid sulfuric), 3% substante volatile, 0,2% cenusa sulfatata si 0,1% aldehide (exprimate in aldehide formica). Avand in vedere faptul ca acidul sorbic are o solubilitate scazuta in apa, se prefera utilizarea sarurilor sale usor solubile: sorbatul de potasiu si sorbatul de calciu (actiunea lor microbiana se desfasoara in mediul apos).

Acidul sorbic este activ impotriva mucegaiurilor si drojdiilor si mai putin ca bacteriostatic si bactericid. Activitatea fungistica si fungicida este potentiata prin adaos de acizi si clorura de sodiu. Acidul sorbic se foloseste ca atare prin incorporare in produs sau sub forma de solutie pentru imersare si stropire. Folosirea acidului sorbic prezinta urmatoarele avantaje: - microorganismele nu dezvolta rezistenta la acid sorbic, asa cum ese cazul la antibiotice; - acidul sorbic si sarurile sale nu reactioneaza cu constituentii produsului, nu afecteaza culoarea, nu inactiveaza si nu distrug vitaminele si enzimele; - nu formeaza complexe cu substantele minerale; - in doze corecte nu afecteaza gustul si mirosul produsului alimentar. Este eficace si fata de mucegaiurile producatoare de toxine. Dupa datele din literatura de specialitate acidul sorbic se utilizeaza pentru: Margarina, unt, maioneza, produse care au un continut mediu de apa, actiunea conservanta manifestandu-se la nivelul fazei apoase care este faza susceptibilala atacul microbian. La margarina si maioneza se utilizeaza in proportie de 1000mg/kg, iar la unt in proportie de 500mg/kg. Grasimi si uleiuri (cu exceptia uleiului de masline), in proportie de 500mg/kg. Branzeturi care sunt atacate in special de mucegaiuri, mai ales in timpul maturari si distributiei. Acidul sorbic nu se utilizeaza in cazul branzeturilor cu mucegai in pasta. Atunci cand adaosul se face prin incorporare, se folosesc concentratii de 1000mg/kg. Deoarece incorporarea acidului sorbic in branzeturi este destul de dificila, se
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prefera stropirea sau imersarea branzeturilor in solutie de sorbati 10-20%, inainte de inceperea maturarii, mai ales daca aceasta se realizeaza la umiditati relative mari. Produsele de panificatie la care se recomanda sa se foloseasca sorbilpalmitatul in proportie de 500mg/kg (fata de faina), deoarece sorbatii de potasiu au actiune inhibitoare fata de drojdiile de fermentare. Sorbilpalmitatul hidrolizeaza in timp. In produsele de cofetarie se recomanda 500-1000mg/kg iar in cremele pentru patiserie aproximativ 2000mg/kg. Produse zaharoase la care adaosul de acid sorbic si sarurile sale se face in scopul protejarii acestor produse fata de drojdiile osmofile, mai ales in cazul martipanului, produselor zaharoase cu umpluturi, cu fructe, etc. Doza admisa este de aproximativ 1000mg/kg. Acidul sorbic nu prezinta eficacitate practica satisfacatoare decat in asociere cu un anumit grad alcoolic si cu un anumit continut de SO2, fiind o substanta care ajuta la micsorarea dozelor de SO2 la conservarea vinurilor imbuteliate. Utilizarea rationala a acidului sorbic la stabilizarea vinurilor dulci impune respectarea urmatoarelor reguli: doza de acid sorbic se va stabilii in functie de gradul alcoolic si de PH-ul vinului; vinurile vor avea un numar redus de drojdii; vinurile se vor sulfita optim pentru a evita oxidarea si dezvoltarea bacteriilor, nu se va utiliza la conservarea vinurilor rosii; se folosesc nu mai solutii proaspete de acid sorbic in solutie alcoolica 10% , respectiv solutie apoasa de sorbati de potasiu 27%. Conform legislatiei viniviticole din Romania, doza maxima de acid sorbic atmisa este de 200mg/l. Se recomanda folosirea acidului sorbic la impregnarea hartiei pentru ambalat unt, margarina, marmelada, la impregnarea capacelor pentru gemuri si jeleuri.
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Dupa legislatia din Romania se admit urmatoarele niveluri de acid sorbic pentru diferite produse alimentare: margarina, maximum 360mg/kg; branzeturi topite, maximum 1000mg/kg; pasta de tomate, maximum 1000mg/kg; legume si fructe congelate, 1000mg/kg; produse vegetale lactofermentate, 1000mg/kg; produse zaharoase, de patiserie, de panificatie, 500mg/kg;

Acidul sorbic este considerat inofensiv pentru om. Aceste substante sunt metabolizate si asimilate. Unii autori insa semnaleaza aparitia unor fenomene alergice in cazul persoanelor sensibile. Irita membranele mucoase si cauzeaza iritatii ale pielii. O opinie contrara arata ca acidul sorbic suprima vitamina B12 din organismul uman. FAO/OMS Pe baza datelor experimentale obtinute pe animale estimeaza ca doza zilnica, admisibila, fara rezerva pentru om , este de maximum 25mg/milocorp.

Manitol
Indulcitorii naturali nutritivi reprezinta cea mai importanta grupa de indulcitori, unii dintre ei, pe langa valoarea energetica, au si o valoare alimentara deosebita, datorita compozitiei lor chimice mai complexe (mierea de albine si siropul de malt). Indulcitorii naturali nutritivi din categoria polialcoolilor (sorbitol, silitol, manitol, dulcitol) sunt folositi in diete pentru diabetici, pentru prevenirea cariilor dentare, reducerea greutatii corporale (in obezitate si in tulburari ale ficatului). Manitolul se gaseste raspandit in natura, in secretiile arborilor de maslin, paltin si frasin si in special in exudatul arborelui Fraxinus ornus L care contine 90% manitol. Se mai gaseste in cafea in diverse ierburi, fructe si flori, in fungi si licheni precum si in unele alge brune.
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Industrial manitolul se obtine prin reducerea electrolitica sau prin hidrogenarea catalitica sub presiune a d glucozei si d fructozei, plecandu-se in special de la siropul de porumb in solutie alcalina. Se mai poate obtine manitol prin hidroliza melasei de trestie, prin fermentarea manitolactica a zaharozei sau melasei, in care caz fructoza este transformata in manitol, iar glucoza in acid lactic, randamentul in manitol fiind mai mic de 18%. Manitolul se poate extrage si din exudatul de Fraxinus prin fierberea acestuia cu alcool etilic sau prin fierberea sub presiune a exudatului, manitolul fiind purificat prin caracterizari repetate din apa fierbinte si decolorat cu ajutorul carbunelui animal. Manitolul se prezinta sub forma de pulbere cristalina de culoare alba sau sub forma de granule, nehidroscopice, inodore cu gust dulce. Gradul de dulce este de 0,45-0,7 fata de cel al zaharozei, considerat egal cu 1. Are greutatea specifica la 20C egala cu 1,487. Este solubil in apa (13% la 14C), putin solubil in alcool (1,2% la 15C si insolubil in eter). Temperatura de topire este de 65-68C, iar punctul de fierbere este de 190C. Peste 100C sublimeaza lent fara descompunere. Are caldura specifica 0,327 pentru intervalul de temperatura 28-100C. PH-ul solutiei 10% manitol este cuprins intre 5 si 8. Aditivul trebuie sa contina minimum 96 Dmenitol raportat la substanta uscata. Produsul trebuie sa contina maximum 0,1% cenusa, maximum 70mg cloruri/kg, maximum 100mg sulfati/kg, maximum 2 mg As/kg, alte metale grele. Manitolul conform actului normativ elaborat pentru tara noastra, prevede folosirea aditivului quantum satis. Acesta se adauga in produse de cofetarie fara adaos de zahar, pe baza de fructe uscate, pe baza de amidon, de cacao, in paste tartinabile pe baza de cacao, de lapte, fructe uscate sau grasimi, toate avand valoare energetica redusa, sau fara adaos de zahar. Deasemenea aditivul este adaugat in guma de mestecat fara zahar, in sosuri, mustar, in produse fine de brutarie, in produse cu destinatie speciala sau in suplimente alimentare dietetice in stare solida.
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Manitolul mai este folosit ca aditiv si in deserturi sau in produse similare, ca, de exemplu, in deserturi aromate pe baza de apa in preparate pe baza de lapte si in produse derivate pe baza de fructe si legume, de oua, deserturi pe baza de cereale precum micul dejun, deserturi pe baza de grasimi, in gemuri, jeleuri, marmelade, fructe cnfiate, preparate diverse, din fructe, toate avand valoare energetica reduse sau fara adaos de zahar. Manitolul este folosit ca edurcolant, substituent al zaharului in dietele diabeticilor. In acest caz este de preferat utilizarea aditivului impreuna cu sorbitolul. Manitolul mai este utilizat in dieta obezilor, precum si a celor care isi controleaza greutatea corporala, este folosit ca laxativ, ca diuretic osmotic. Manitolul, in general, este bine tolerat de organismul uman, dar nu se recomanda folosirea lui in doze mai mari de 50g/zi. Poate provoca tulburari gastrointestinale. Este interzisa utilizarea sa in alimentatia sugarilor, deoarece poate provoca afectiuni renale.

Mannitol as salvage treatment for Complex Regional Pain Syndrome Type I

Introduction Complex Regional Pain Syndrome Type I (CRPS I), formerly known as reflex sympathetic dystrophy or Sudecks dystrophy, is a painful, potentially disabling syndrome that usually affects the distal part of the extremity. The disorder is characterised by a variety of autonomic and vasomotor disturbances, of which diffuse pain, spreading edema, temperature disturbances, colour changes and functional impairment are most prominent.16,18 In spite of a clear clinical picture, the underlying pathophysiology is largely unclear. In 1942, Sudeck13 hypothesised that an excessive inflammatory reaction causes the syndrome. There is indeed clinical and experimental evidence that an excessive regional inflammatory response, including the production of reactive oxygen free radicals, is involved in CRPS I and causes tissue damage.6,9,15,16 Our group initiated the treatment with radical scavengers such as dimethyl sulfoxide (DMSO) and mannitol3,4 followed by others who reported a beneficial effect of various free radical scavengers on CRPS I including dimethyl sulfoxide, N-acetylcysteine and vitamin C.11,20,21 In The Netherlands, intravenous mannitol for patients with CRPS I has been administered on a large scale because it seemed to be very effective and its side effects were benign. Evaluation of routine treatment with mannitol in CRPS I patients did not prove any benefit.10 In our hospital, mannitol is only administered in patients who do not respond to initial treatment with radical scavengers like dimethyl sulfoxide (DMSO) ointments or Nacetylcysteine

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Methods Study design This is a retrospective observational study of consecutive patients with CRPS I receiving intravenous mannitol as salvage therapy between 1990 and 2004. Mannitol infusion is part of a multimodal step-up treatment protocol, which was applied to these patients (Table 1). We introduced the term salvage for the mannitol treatment indicating that mannitol was used as final step in free radical scavenger treatment when other (more conservative) treatments alone or in combinations had failed. Mannitol is to our knowledge the strongest radical scavenger available necessitating intravenous administration and therefore hospital admission. This protocol was kept unchanged during the study period. Patients entered the study in case of being non-responders. Nonresponders were defined as patients who did not improve in signs and symptoms within 2 weeks after initiation of treatment according to the first part of the protocol or had recurrent CRPS I after initial success with mannitol. Diagnosis of CRPS I CRPS I was diagnosed using the following diagnostic criteria according to Veldman et al.16: 1. Presence of at least four of the following five signs and symptoms: (a) unexplained diffuse pain and tenderness in the distal part of the extremity; (b) difference in skin colour in relation to the healthy symmetrical limb; (c) diffuse edema; (d) difference in skin temperature relative to the healthy symmetrical limb; (e) limited range of movement. 2. The above signs and symptoms increased during exercise. 3. The above signs and symptoms were present in an area much larger than the area of primary injury or operation and included the area distal to the primary injury.

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CRPS I was divided into warm and cold based on results of vasomotor instability. Vasomotor instability was determined by three measurements of skin temperature under resting conditions (room temperature with adaptation for 30 min) with infrared thermometry (Generic Sherwood Digital Ear Thermometer) during the first visit. Any mean difference of two or more degrees Celsius in skin temperature between the symptomatic and non-symptomatic extremity was considered significant. Three groups of CRPS I patients were distinguished: first onset (acute) CRPS I, relapse of CRPS I and chronic CRPS I (symptoms for more than 3 months). Mannitol treatment Mannitol 10% was administered in a volume of 1 l per 24 h for 710 days preferably by subclavian vein infusion. Patients were hospitalised during mannitol treatment and continued other protocol therapies if applicable. Data collection Demographic data included age, gender, affected extremity, initial trauma, time between onset of symptoms and diagnosis, and time between diagnosis and mannitol treatment, smoking habits and past medical history. Signs and symptoms of CRPS I and possible side effects of the treatment were prospectively documented in a computerised patient record file before and after 1 week, 1 month and 1 year after mannitol treatment.

Primary outcome The effect of mannitol treatment (minimum 5 days, clinical effects within 48 h after start treatment) was evaluated per sign and per symptom at consultation and start of mannitol treatment,
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and after 1 month. When a sign or symptom of CRPS I had disappeared it was called an improvement, when is persisted or worsened it was called no improvement. In some cases in which these signs and symptoms were not accurately documented, chart notes indicating good or excellent response and notes indicating fair or poor response to treatment were considered improvement and no improvement, respectively. Overall improvement (resolution of CRPS I according to Veldman et al.16 criteria) is defined as less than three of the following symptoms present (pain, swelling, edema, temperature difference, loss of range of motion and increase after exercise. The overall effect of mannitol treatment during follow-up was recorded in a dichotomous way: improvement or no improvement. Data analysis Results were analysed for the whole group and for the subgroups acute CRPS I, relapsing CRPS I and chronic CRPS I. Second mannitol treatments (n = 32) were considered as new treatment after correction for depending observations using the Generalised Estimating Equations (GEE, see following section).19 For several symptoms, a correction for possible confounding factors was performed: pain was corrected for the use of analgesic, difference in skin colour and skin temperature were corrected for the use of vasodilatation treatment, unexplained limited range of motion was corrected for physiotherapy and finally muscle spasm for the use of muscle cramp therapy.

Statistics Statistical analysis was performed using a logistic regression model with effect of mannitol treatment as dependent variable and all clinical parameters as independent variables. Odds ratios,
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including their 95% confidence limits, were used to describe the association between overall improvement and presence of absence of individual symptoms before and after mannitol treatment. Thirty-two patients were treated twice with mannitol. Simply using cross tabs or logistic regression will therefore give biased parameter estimates and odds ratios. To deal with this problem, a specific linear regression model was used, which is known as the Generalised Estimating Equations (GEE) approach.19 This technique corrects for depending observations by modelling correlations between subjects. To find out which factors could have prognostic value on the effect of mannitol treatment, a univariate analysis between the effect of mannitol treatment and all possible predicting variables (age, gender, skin temperature, affected extremity, type of CRPS I, smoking behaviour and previous mannitol treatment) was performed first and again using the GEE approach. Correction for possible confounding factors is easily performed in the GEE approach by inserting the confounder as a second independent variable in the model.Weused the GEE model with an exchangeable correlation structure to correct for the repeated measurements within one person. Intra-patients correlations coefficients ranged from 0.10 to 0.33 for the several different analyses. Relations were considered significant when p < 0.05. A number of variables were thus selected, which seemed to be of use in predicting the effect of mannitol treatment. As a result, they were all inserted together in one model. This model estimates the probability of an adverse outcome of treatment for CRPS I. Results were considered significant when p < 0.05.

Results More than one thousand patients with CRPS I were treated according to a standard treatment protocol from 1990 until 2004. Only 68 patients (3%), 54 females and 14 males underwent a total
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of 100 mannitol infusions as salvage treatment. Median age was 32.4 years (range 2077 years). Sixty-four patients (94%) were seen at their first visit by one surgeon. In 30 patients, the upper extremity was affected, in 37 patients the lower extremity and in one patient both the upper and lower extremities. CRPS I was due to trauma (e.g.: sprain, fracture, wound) in 70%, to surgery in 15% and to peripheral intravenous line insertion in 2%. In 10 patients (15%) no cause was reported. The median interval between trauma and CRPS I symptoms was 27 days (range 1795 days). The median interval between CRPS I symptoms and first visit to the outpatient clinic was 40 days (range 1781 days). The median interval between trauma and start of mannitol treatment was 129 days (range 31046 days). Patient who were treated twice had shorter time intervals. Indications for mannitol treatment include 58 mannitol treatments for acute CRPS I, 19 mannitol treatments for relapse of CRPS I and 23 treatments for exacerbation of chronic CRPS I (a history of more than 3 months). The median period of mannitol infusion was 7 days (range 510 days). Clinical effects of mannitol infusion were seen within 2448 h after start treatment. Side effects of mannitol treatment were not observed. Sixty-nine of the 100 mannitol treatments was administrated through a central intravenous (subclavian) catheter. Catheter related complications occurred in five patients. Thoracic drainage for an iatrogenic pneumothorax had to be performed once (1.4%). Removal of an infected catheter with clinical sepsis, not interfering with successful mannitol infusions, occurred four times (5.8%). From the 31 (31%) mannitol treatments by peripheral intravenous catheter, superficial phlebitis had to be treated three times (9.7%). The effect of mannitol treatment on signs and symptoms of CRPS I in all patients are listed in Table 2A. Evaluating the effect of mannitol per sign or symptom after 1 month; pain was decreased in 79% of all CRPS I patients. Functional improvement after mannitol treatment was 61% after 1 month. There was an overall improvement of 24% after 1 week and 30% after 1 month. In Table 2B the relative chance on overall improvement is
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demonstrated per sign or symptom after mannitol treatment. For example if pain is present, there is a chance of 30.4% after mannitol treatment on overall improvement. Overall improvement was significantly correlated (p < 0.001) with initially warm CRPS I compared to patients with cold CRPS I (OR = 6.30 with CI [2.37 16.75]). Discussion The current study is the largest study in which the effect of mannitol treatment as part of a multimodal approach in patients with CRPS I is evaluated. Evaluation of this regimen demonstrates that mannitol has limited effect in patients with CRPS I on relief of signs and symptoms. Mannitol 10% is known for its hyperosmolar effect, but in this setting, acts as a free radical scavenger in CRPS I, directed at the hydroxyl radical.8 At this dosage, the total amount of mannitol (100 g per 24 h) is too low to induce hyperosmolar effects. Intravenously administered mannitol is metabolised in 7% and excreted in the urine in 93% within 24 h. The elimination half-life of mannitol is 15100 min. Mannitol is widely used in the control of raised intracranial pressure following brain injury, treatment of glaucoma and in the prevention of post-ischemic acute tubular necrosis. From these studies we know that mannitol treatment is generally well tolerated, although care should be taken in patients with renal failure because hyperosmolality may occur.17 When renal function is normal, osmolality does not increased significantly. In our study no side effects were documented. The conclusion of that study was that mannitol changed the inflammatory signs and impaired oxygen extraction. Zyluk presented results of 30 patients treated with mannitol, in which the hand strength was improved and a regression of typical changes in bone scintigraphy was observed.22 Smeets described 46 mannitol treatments in 28 patients with observed improvement in 65% of the treatments.12 Since 1982, we started treating
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CRPS I patients with free radical scavengers like dimethyl sulfoxide ointments, N-acetylcysteine and mannitol. Because the clinical effects were hopeful and no side effects occurred, a standard multimodal step-up protocol including mannitol was introduced for all patients with CRPS I since 1990 (Table 1).11,14 Bannink showed poor results of mannitol treatment in a small randomised trial of patients with CRPS I.1 This study was only published as an abstract but results were confirmed by a larger, randomised, placebo-controlled study of the same group.10 It is tempting to conclude that mannitol has no effect in the treatment of CRPS I patients based on results of this prospective randomised placebo-controlled study and that of our large retrospective observational study. However, there are marked differences between the studies apart from the design. Perez et al. used the Bruehl criteria of CRPS I for inclusion2,10 and we used the Veldman et al. criteria which differ in terms of sensitivity and specificity. The patient population studied by Perez et al. consisted of 22 patients, having a median duration of symptoms of 6.5 months and 12 suffering from CRPS I for more than 1 year before treatment in contrast to a median interval between CRPS I symptoms and outpatient clinic was 40 days in our population. This implies that the tendency for better outcome with earlier (acute) intervention shown in the present large series might not have been captured in their small series. Another important difference is that Perez used mannitol in consecutive CRPS I patients whereas we used mannitol in a step-up protocol as salvage therapy for more persistent CRPS I patients. Although the study was small, Perez and others found the same predictive factors for adverse treatment outcome, e.g. initial cold CRPS I and lower extremity as we did, most likely because in both studies patients with initial cold CRPS were overrepresented (69% and 65%, respectively). A weakness of our study is the retrospective design with subsequent large percentages of missing data, which reduce the internal validity. Gathering complete data is especially important

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in a study of patients with CRPS I, because the presentation of the disease is not uniform but merely a combination of signs and symptoms. Therefore, recoding with dichotomisation of clinical data was performed. It is well accepted that treatment of CRPS I needs an individualised therapeutic strategy throughout the course of the disease. To correct for parallel treatments, which may bias the treatment effect of mannitol, a statistical analysis described in this study was used to evaluate the overall effect of mannitol treatment. Generalised Estimating Equations is one of the most commonly used modelling techniques to conduct logistic regression analysis for correlated dichotomous responses.7 It produces odds ratios as association measures, comparable with standard logistic regression. Mannitol could not be identified to contribute substantially to the successful treatment of all patients with CRPS I (69.6%). Based on the findings of our study, together with the results of this randomised clinical trial and considering the national published guidelines on CRPS I in the Netherlands, in which mannitol treatment is not recommended as standard treatment, we decided to stop treating CRPS I patients with mannitol as salvage therapy in our practice. For patients with acute, warm CRPS I in the upper extremity, mannitol seems beneficial. A prospective randomised, placebo-controlled clinical trial is mandatory prior to integration of mannitol to a standard treatment strategy in this selected category of patients with CRPS I. Conclusion This large study of 100 mannitol treatments demonstrates that mannitol does not clearly provide benefit to the patient with CRPS I in terms of relief of signs and symptoms. We therefore do not advise mannitol administration as salvage therapy for patients with persistent CRPS I.

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References 1. Bannink IMJ, Vranken JH, Perez RSGM, et al. Treatment of CRPS type 1 with intravenous mannitol as an oxygen radical scavenger. Eur J Anaesth 2000; 19(Suppl.):183. 2. Bruehl S, Harden RN, Galer BS, et al. External validation of IASP diagnostic criteria for Complex Regional Pain Syndrome and proposed research diagnostic criteria. International Association for the Study of Pain. Pain 1999;81:14754. 3. Goris RJA. Treatment of reflex sympathetic dystrophy with hydroxyl radical scavengers. Unfallchirurg 1985;88:3302. 4. Goris RJA, Dongen LM, Winters HA. Are toxic oxygen radicals involved in the pathogenesis of reflex sympathetic dystrophy? Free Radic Res Commun 1987;3:138. 5. Goris RJA. Reflex sympathetic dystrophy: model of a severe regional inflammatory response syndrome. World J Surg 1998;197202. 6. Heerschap A, den Hollander JA, Reynen H, Goris RJA. Metabolic changes in reflex sympathetic dystrophy: a 31P NMR spectroscopy study. Muscle Nerve 1993; 16:36773. 7. Liang KH, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika 1986;73:1322. 8. Magovern Jr GJ, Bolling SF, Casale AS, et al. The mechanism of mannitol in reducing ischemic injury: hyperosmolarity or hydroxyl scavenger? Circulation
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1984;70:I915. 9. Oyen WJG, Arntz IE, Claessens RAMJ, et al. Reflex sympathetic dystrophy of the hand: an excessive inflammatory response? Pain 1993;55:1517. 10. Perez RS, Pragt E, Geurts J, et al. Treatment of patients with complex regional pain syndrome type I with mannitol: a prospective, randomized, placebocontrolled, double-blinded study. J Pain 2008;8:67886. 11. Perez RS, Zuurmond WW, Bezemer PD, et al. The treatment of complex regional pain syndrome type I with free radical scavengers: a randomized controlled study. Pain 2003;102:297307. 12. Smeets PMJH, van den Wildenberg FA, Crebolder HFJM, Weber WE. Prospectieve studie van 46 infuusbehandelingen thuis met mannitol bij 28 patienten met sympathische reflex dystrofie. NTPP 1999;19:2533. 13. Sudeck P. Die sogenannte akute Knochenatrophie als Entzu ndungsvorgang. Der Chirurg 1942;15:44958. 14. van der Laan L, Goris RJA. Reflex sympathetic dystrophy. An exaggerated regional inflammatory response? Hand Clin 1997;13:37385. 15. van der Laan L, Kapitein PJC, Verhofstad AAJ, et al. Clinical signs and symptoms of acute reflex sympathetic dystrophy in one hindlimb of the rat, induced by infusion of a free-radical donor. Acta Orthop Belg 1998;64:2107. 16. Veldman PHJM, Reynen HM, Arntz IE, Goris RJA. Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients. Lancet 1993;342: 10126.

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17. Wakai A, Roberts I, Schierhout G. Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev 2007;CD001049. 18. Wasner G, Schattschneider J, Baron R. Skin temperature side differencesa diagnostic tool for CRPS? Pain 2002;98:1926. 19. Zeger SL, Liang KY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986;42:12130. 20. Zollinger PE, Tuinebreijer WE, Kreis RW, Breederveld RS. Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomised trial. Lancet 1999;354:20258. 21. Zuurmond WW, Langendijk PN, Bezemer PD, et al. Treatment of acute reflex sympathetic dystrophy with DMSO 50% in a fatty cream. Acta Anaesthesiol Scand 1996;40:3647. 22. Zyluk A. Clinical estimation of late treatment results in posttraumatic Sudecks dystrophy treated with mannitol, calcitonin and exercise therapy. Ann Acad Med Stetin 1994;40:13344. E.C.T.H. Tan et al. / Injury, Int.

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Manitol ca tratament de salvare pentru Complexul de tip Regional sindrom de durere I

Introducere Complexul regional Pain Sindromul de tip I (CRPS I), fost Cunoscut i drept distrofia simpatica reflexa sau distrofie Sudecks, este un sindrom dureros, potential dezactivarea care afecteaza, de obicei, parte distanta a extremitilor. Tulburare este caracterizata printr-o varietate de tulburri vegetative i vasomotorii, din care dureri difuze, edem rspndire, tulburri de temperatur, de culoare modificrile i depreciere funcionale sunt cele mai prominent.16, 18 n ciuda unui tablou clinic clar, fiziopatologia care stau la baza este n mare msur neclar. n 1942, Sudeck13 emis ipoteza c o reacie inflamatorie excesiv provoac sindromul. exist ntr-adevr, clinice si experimentale dovezi c o excesiv rspuns inflamator regionale, inclusiv producia de reactive de oxigen radicalii liberi, este implicat n CRPS I i cauzele esut damage.6, 9,15,16 Grupul nostru a iniiat tratamentul cu necrofagi radicale, cum ar fi dimetilsulfoxid (DMSO) i mannitol3, 4 urmat de altele care au raportat un efect benefic din diverse necrofagi de radicali liberi pe CRPS I, inclusiv de dimetil sulfoxid, N-acetilcisteina i vitamina C.11, 20,21 n rile de Jos, manitol intravenoas la pacienii cu CRPS I a fost administrat pe o scar larg, deoarece se prea fi foarte eficiente, iar efectele sale secundare au fost benigne. evaluarea tratamentul de rutin cu manitol la CRPS pacienii I nu a dovedit orice benefit.10 n spitalul nostru, manitol se administreaz numai n

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pacienii care nu rspund la tratamentul iniial cu radical necrofagi, cum ar fi Dimetil sulfoxid (DMSO) sau unguente Nacetylcysteine Metode Studiu de design Acesta este un studiu retrospectiv observational de consecutiv pacienii cu CRPS am primit manitol intravenos ca salvare Terapia ntre 1990 i 2004. Perfuzie manitol este parte a unui multimodal step-up protocolul de tratament, care a fost aplicat aceti pacieni (Tabelul 1). Am introdus termenul de "salvare" pentru Tratamentul manitol indic faptul c manitol a fost folosit ca ultim pas n tratamentul scavenger de radicali liberi, atunci cnd alte (mai conservator) tratamente n monoterapie sau n combinaii au euat. Manitol este de a cunotinele noastre mai puternic scavenger de radicali liberi disponibile necesitnd administrarea intravenoas i, prin urmare, de admitere spital. Acest protocol a fost pstrat neschimbat pe parcursul perioadei de studiu. Pacienii au intrat n studiu, n cazul de a fi non-rspuns. Nonresponders au fost definite ca pacientii care nu au semne de mbuntire n i simptome n termen de 2 sptmni dup iniierea tratamentului n conformitate cu prima parte a protocolului sau a avut CRPS recurente I Dupa succesul iniial cu manitol. Diagnosticul de CRPS I CRPS Am fost diagnosticat, utiliznd urmtoarele criterii de diagnostic n conformitate cu Veldman et al.16:
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1. Prezena a cel puin patru din urmtoarele cinci semne i Simptome: (a) durere inexplicabil difuz i sensibilitate n partea distal a extremitilor; (b) diferena de culoare a pielii, n ceea ce privete nivelul membrelor simetric sntos; (c) edem difuz; (d) diferena de temperatur relativ la pielea sanatoasa simetrice membrelor; (e) gam limitat de micare. 2. De semne i simptome de mai sus a crescut in timpul exercitiilor fizice. 3. De semne i simptome de mai sus au fost prezente ntr-o zon mult mai mare dect zona de prejudiciu primare sau operaiunii i incluse distal de zona de prejudiciu primar. CRPS Am fost mprit n "cald" i "rece", pe baza rezultatelor de vasomotorii instabilitate. Instabilitate vasomotorie a fost determinat de trei msurtori ale temperaturii pielii n condiii de repaus (Temperatura camerei cu adaptare timp de 30 min) cu infrarou termometriei (Generic Sherwood digital Termometru ureche) n timpul prima vizita. Orice diferen medie de dou sau mai multe grade Celsius n temperatura pielii ntre simptomatic i non-simptomatic Extremitatea a fost considerat semnificativ. Trei grupuri de CRPS I pacieni au fost distinse: prima instalare (acut) I CRPS, recidiva a CRPS I i CRPS cronice I (simptome pentru mai mult de 3 luni). Manitol tratament Manitol 10% a fost administrat ntr-un volum de 1 litru la fiecare 24 h pentru 7-10 zile de preferin prin perfuzie vena subclavie. Pacienii au fost spitalizat n timpul tratamentului manitol i a continuat alte protocol terapii dac este cazul.
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Colectarea datelor Datele demografice au inclus vrsta, sexul, extremitatea afectat, trauma initiala, de timp dintre debutul simptomelor i diagnostic, precu m i de timp ntre diagnostic i tratament manitol, obiceiurile fumat i trecutul medical. Semne si simptome de CRPS I i posibilele efecte secundare ale tratamentului au fost documentate prospectiv ntr-un fiier electronic de nregistrare pacient nainte i dup 1sptmna, 1 lun i 1 an dup tratament cu manitol. Rezultat primar Efectul tratamentului manitol (minimum 5 zile, clinic efecte n 48 de ore de la nceperea tratamentului) a fost evaluat pe semnul i pe simptom, la consultarea i nceputul tratamentului manitol, i dup 1 lun. Atunci cnd un semn sau simptom al CRPS am avut disprut a fost numit un "mbuntire", atunci cnd este persistat sau nrutit a fost numit "nicio mbuntire". n unele cazuri n care aceste semne i simptome nu au fost corect documentate, diagram note, care indic rspunsul bun sau excelent i note, care indic Rspunsul corect sau slab la tratament au fost luate n considerare mbuntirea si nici o imbunatatire, respectiv imbuntirea general (rezoluie de CRPS I n conformitate cu Veldman et al.16 criterii) este definit ca mai puin de trei urmtoarele simptome prezente (durere, tumefiere, edem, temperatura diferen, pierderea de gam de micare i creterea dupa antrenament. Efectul global al tratamentului manitol timpul follow-up a fost nregistrat ntr-un mod dihotomic: mbuntirea sau nici o mbuntire.

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Analiza datelor Rezultatele au fost analizate pentru ntregul grup i pentru subgrupuri CRPS acute I, recurent CRPS I i cronice CRPS I. n al doilea rnd tratamente manitol (n = 32) au fost considerate ca nou tratament, dup corecia n funcie de observaiile folosind Ecuaiile generalizate estimarea (GEE, a se vedea seciunea urmtoare) . Pentru mai multe simptome, o corecie de confuzie posibil factori a fost realizat: durere a fost corectat pentru utilizarea de analgezice, diferena de culoare a pielii i temperatura pielii au fost corectate pentru utilizarea tratamentului vasodilataie, gama limitat de inexplicabil Moiunea a fost corectat pentru fizioterapie i, n final spasme musculare pentru utilizarea terapiei crampe musculare. Statistic Analiza statistic a fost realizat cu ajutorul unui regresie logistic model cu "efect de tratament manitol" ca variabil dependent i toi parametrii clinici, ca variabile independente. Cote raporturi, inclusiv limitele lor de ncredere de 95%, au fost folosite pentru a descrie asociere ntre mbuntire general i prezena absenei simptomelor individuale, nainte i dup tratament manitol. Treizeci si doi de pacienti au fost tratati de doua ori cu manitol, pur i simplu folosind file cruce sau de regresie logistica va oferi, prin urmare, prtinitoare. Estimrile parametrilor i raportul de cote. Pentru a rezolva aceast problem, o specifice unui anumit model de regresie liniara a fost folosit, care este cunoscut sub numele de Ecuaiile generalizate estimarea (GEE) approach.19 Aceast Tehnica corecteaz n funcie de
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observaiile de modelare corelaiilor dintre subieci. Pentru a afla care sunt factorii care ar putea avea o valoare prognostic pe efectul tratamentului manitol, o analiz univariat ntre efectul tratamentului manitol i toate variabilele posibile prezic (vrst, sex, temperatura pielii, extremitatea afectat, tipul de CRPS I, comportamentul fumat si tratament anterior manitol) a fost efectuat primul i folosind din nou abordarea GEE. Corecie pentru posibili factori este uor de realizat n abordarea GEE prin introducerea confounder ca un al doilea variabil independent n model.Weused modelul GEE cu o Structura de coresponden schimbate pentru a corecta repetate msurtori n termen de o persoan. Intra-pacieni corelaii Coeficienii de variat 0.10 la 0.33 pentru mai multe diferite analize. Relaiile au fost considerate semnificative atunci cnd p <0,05.A Numrul de variabile au fost selectate astfel, ceea ce prea a fi de utilizare n estimarea efectului tratamentului manitol. Ca urmare, acestea au fost toate introduse mpreun ntr-un singur model. Acest model estimeaz probabilitatea unui rezultat negativ de tratament pentru CRPSI. Rezultatele au fost considerate semnificative atunci cnd p <0,05. Rezultate Mai mult de o mie de pacienti cu CRPS I au fost tratai n conformitate cu un protocol de tratament standard din 1990 pn n 2004. Numai 68 pacieni (3%), 54 femei i 14 brbai a suferit un total din 100 perfuzii manitol ca tratament de salvare. Vrsta medie a fost 32.4 ani (interval 20-77 ani). aizeci i patru de pacieni (94%) au fost observate la prima lor vizit de un chirurg. n 30 de pacieni, superioare extremitatea a fost afectat, la 37 de pacieni inferior i la un pacient att
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de sus cat i inferioare. CRPS am fost din cauza la traume (de exemplu: entorsa, fractura, rana), n 70%, la interventii chirurgicale la 15% i de introducerea periferice linia intravenoas la 2%. n 10 pacieni (15%), nici o cauza a fost raportat. Intervalul median ntre traum CRPS i simptomele I a fost de 27 zile (interval 1-795 zile). Median Intervalul dintre CRPS I simptome i prima vizit n ambulatoriu Clinica a fost de 40 zile (interval 1-781 zile). Intervalul median ntre traum i nceperea tratamentului a fost de 129 zile manitol (Interval 3-1046 zile). Pacientul care au fost tratai de dou ori mai scurt avut intervale de timp. Indicatii pentru tratament includ manitol 58 tratamente manitol pentru CRPS acute I, 19 tratamente manitol pentru recidiv a CRPS I i 23 de tratamente pentru exacerbarea cronice CRPS I (o istorie de mai mult de 3 luni). Perioada medie de perfuzie manitol fost de 7 zile (zile interval 5-10). Efectele clinice ale manitol perfuzie au fost observate n termen de 24-48 de ore dup tratament de pornire. Efectele secundare ale tratamentului manitol nu au fost respectate. aizeci i nou de 100 de tratamente manitol fost administrate prin intermediul unei centrale intravenoas (subclavie) cateter. Complicaii legate de cateter au avut loc n cinci pacieni. Drenaj toracic pentru o iatrogena pneumotorax a trebuit s fie realizat o singur dat (1,4%). ndeprtarea unei cateter infectat cu sepsis clinic, nu interfereaz cu infuzii de succes manitol, au avut loc patru ori (5,8%). De la cele 31 (31%), tratamente de manitol intravenoas periferic cateter, flebita superficiala a trebuit s fie tratai de trei ori (9,7%). Efectul tratamentului cu manitol pentru semne i simptome de Am CRPS la toi pacienii sunt enumerate n Tabelul 2A. Evaluarea efectului manitol pe semn sau simptom dup 1 lun, durerea a fost redus la 79% din totalul pacienilor CRPS I. mbuntire funcional dup tratament a fost de 61%, manitol dupa 1 luna. Nu a fost un general mbuntirea de 24% dup 1 sptmn, iar 30% dupa 1 luna.
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Discuie Studiul actual este cel mai mare studiu in care efectul de Tratamentul manitol, ca parte a unei abordri multimodale la pacienii cu CRPS I este evaluat. Evaluarea acestui regim demonstreaz manitol c a limitat efectul la pacienii cu CRPS I pe ameliorarea semne i simptome. Manitol 10% este cunoscut pentru efectul su hiperosmolar, dar n acest setare, acioneaz ca un scavenger de radicali liberi gratuit n CRPS I, ndreptate la hidroxil radical. La aceast doz, suma total de manitol (100 g pentru 24 ore) este prea mic pentru a induce efecte hiperosmolar. Manitol administrate intravenos este metabolizat la 7% i excretat n urin n 93% n termen de 24 de ore. De njumtire de manitol este 15-100 min. Manitol este utilizat pe scar larg n controlul de presiune intracranian crescut n urma leziuni cerebrale, tratamentul glaucom i n prevenirea post-ischemic acut tubular necroz. Din aceste studii, tim c tratamentul este manitol in general bine tolerat, dei ar trebui s fie luate de ngrijire la pacienii cu insuficien renal, deoarece hyperosmolality poate occur.17 Cnd funcia renal este normal, osmolalitatea nu a crescut n mod semnificativ. n studiul nostru nu are efecte adverse au fost documentate. Concluzia acestui studiu a fost ca manitol schimbat semne inflamatorii i de extracie de oxigen depreciate. Zyluk Rezultatele prezentate de 30 de pacieni tratai cu manitol, n care puterea de mn a fost mbuntit i un regres de tipic schimbri n scintigrafie osoas a fost descris observed.22 Smeets 46 tratamente manitol la 28 de pacienti cu mbuntirea observat n 65% din treatments.12 Din 1982, am nceput tratarea CRPS Am pacieni cu necrofagi de radicali liberi, cum ar fi de dimetil
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unguente sulfoxid, N-acetilcisteina i manitol. Deoarece Efectele clinice au fost plini de speranta si nici efecte secundare au avut loc, un standard de multimodal step-up, inclusiv protocolul a fost manitol introdus pentru toti pacientii cu CRPS I din 1990 (tabelul 1) .11,14 Bannink au avut rezultate slabe ale tratamentului manitol ntr-o mic studiu randomizat de pacienti cu CRPS I.1 Acest studiu a fost de numai publicat ca un rezumat, dar rezultatele au fost confirmate de o mai mare, randomizat, controlat cu placebo studiu a group.10 acelai Acesta este tentant s concluzionm c manitol are nici un efect n tratamentul CRPS de pacieni I, pe baza rezultatelor acestui studiu randomizat prospectiv studiu controlat cu placebo i a posteriori noastr mare observaional de studiu. Cu toate acestea, exist diferene marcate ntre studiile n afar de proiectare. Perez Criteriile Bruehl de CRPS I, pentru inclusion2, 10 i am folosit Veldman criterii care difer n termeni de sensibilitate i specificitate, populaie de pacieni studiat de Perez et al. a constat din 22 de pacieni, avnd o durat medie a simptomelor de 6,5 luni i 12 care sufer de CRPS I pentru mai mult de 1 an nainte de nceperea tratamentului, spre deosebire de un interval median ntre CRPS simptome I i clinica de ambulatoriu a fost de 40 de zile n populaia noastr. Acest lucru implic faptul c tendina de rezultate mai bune cu mai devreme (acut) de intervenie se arat n serie mare de fa nu ar fi fost capturat n lor serii mici. O alt diferen important este aceea c Perez utilizat manitol n CRPS consecutive I pacienilor ntruct le-am folosit manitol ntr-un protocol pas-up ca terapie de salvare pentru CRPS mai persistente I pacieni. Dei studiul a fost mic, Perez i alii gsit aceleai factori predispozani pentru rezultatul tratamentului advers, de exemplu, iniial CRPS reci I i extremitatea inferior, aa cum am fcuto, cel mai probabil pentru c n ambele studii pacienii cu CRPS iniiale au fost supra-reprezentate la rece (69% i 65%, respectiv).
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O slbiciune a studiului nostru este de design retrospectiv, cu ulterioare procente mari de date lips, care reduc intern de valabilitate. Colectarea de date complete este deosebit de important. ntr-un studiu de pacienti cu CRPS I, din cauza prezentare a bolii nu este uniform, ci doar o combinaie de semne i simptome. De aceea, recodificare cu dichotomisation de Datele clinice au fost efectuate. Este bine acceptat faptul c tratamentul CRPS Am nevoie de o strategie terapeutic individualizat de-a lungul cursul bolii. Pentru a corecta pentru tratamente paralele, care poate prtinire Efectul tratamentului cu manitol, o analiz statistic descrise n acest studiu a fost utilizat pentru a evalua efectul global al manitol tratament. Ecuaii generalizate Estimarea este una dintre tehnicile cele mai frecvent utilizate de modelare a efectua logistice Analiza de regresie pentru corelat dihotomic responses.7 Se produce raporturi cote ca msuri de asociere, comparabile cu standard de regresie logistic. Manitol nu a putut fi identificat pentru a contribuie n mod substanial la tratarea cu succes a tuturor pacienilor cu CRPS I (69,6%). Pe baza concluziilor studiului nostru, mpreun cu rezultatele acestui studiu clinic randomizat, i avnd n vedere naionale de orientrile publicate pe CRPS I n rile de Jos, n care tratamentul nu este recomandat manitol ca standard tratament, ne-am decis pentru a opri tratarea CRPS I pacienilor cu manitol ca terapie de salvare n practica noastr. Pentru pacienii cu CRPS acute, calde I, n extremitatea superioar, manitol pare benefic. Un studiu prospectiv randomizat, controlat cu placebo clinice proces este obligatorie nainte de integrarea manitol la un standard strategie de tratament n aceast categorie de pacieni cu selectia CRPS I. Concluzie Acest mare studiu de 100 de tratamente cu manitol, demonstreaz c manitol nu prevede n mod clar beneficii pentru pacient cu CRPS I n ceea ce privete ameliorarea semnelor i simptomelor. Noi, prin urmare, nu recomandam administrarea cu manitol ca terapie de salvare pentru pacientii cu persistenta CRPS I.
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BIBLIOGRAFIE

bob

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