Extracorporeal Detoxification Methods in the Treatment of Destructive Pancreatitis

The rise in the incidence of acute necrotic pancreatitis in the past decade and high mortality rates of as high as 20—45% all suggest that the disease is of high social, medical, and economic importance. Objective: to study the efficiency of extracor� poreal detoxification methods in the combination treatment of patients with severe destructive pancreatitis. Subjects and methods. The investigation enrolled 20 patients aged 40 to 53 years with destructive pancreatitis treated in the intensive care unit, Almaty City Clinical Hospital Four. Results and discussion. Analysis of the findings over time could reveal that early incorporation of extracorporeal detoxification methods in the combination treatment of pancreatic necrosis provides a reduction in the clinical signs of endotoxicosis, which could prevent anuric acute renal failure in 61% of the cases and com� pletely safeguard against multiple organ dysfunction in 22%. The investigation showed the necessity and efficiency the early use of albumin dialysis, hemodiafiltration in the combination treatment of sepsis and septic shock in destructive pancreati� tis, leading to a significant reduction in mortality rates. The maximum detoxification potential of albumin dialysis in sepsis complicating the course of destructive pancreatitis is achieved by a combination of different mechanisms for elimination of toxic substances, such as convection, sorption, and diffusion, in the extracorporeal circuit. Conclusion. Early use of extra� corporeal detoxification methods in patients with severe destructive diseases of the pancreas results in a significant reduc�


Introduction
Despite considerable achievements in modern medi cine, abdominal sepsis remains one of the most severe com plications of surgical infections and has the highest mor
One of the reasons that lead to the development of abdominal sepsis is the acute destructive pancreatitis or pancreatic necrosis.Increased incidence of pancreatitis in the last decade [2], a relatively young and working age majority of patients -from 25 to 60 years [3], the increased duration of treatment and costs [4][5][6], and high mortality rate (up to 20-45% [7,8]) testify for the high social, medical and economic importance of this patholog ic condition.The increased variability of clinical patterns including complications, the most dangerous of which include multiple organ failure (MOF), peritonitis, sepsis, pyogenic cellulitis of retroperitoneal fat and arrosive bleeding [9].The most dangerous period includes hemody namic disorders and pancreatogenic shock.The high mor tality rate is due to pathogenic features of destructive pan creatitis accompanied by increased intoxication, release of a large number of inflammatory mediators (IL 6, IL 8, IL 10, TNF α) into the blood, translocation of middle and low toxic substances from the gastrointestinal tract into the blood.As a result, a «mediator chaos» and MOF are devel oping.Treatment of MOF is far from solving problem of resuscitation.Despite the increasing knowledge of patho physiological processes, the emergence of new generations of antibacterial drugs, improving of life support technolo gy and surgical techniques, MOF is a major cause of mor tality in the intensive care units, mainly because of devel opment of severe sepsis and septic shock.In recent years, research interest has been aroused with the evaluation of perspectivity of the early onset of extended renal replace ment therapy (RRT) in sepsis with no need in waiting for the expanded clinical and laboratory MOF picture, in order to prevent its development.However, the objective criteria for the early start of RRT have not been thori ugthly clarified.On the one hand, the beginning of RRT in sepsis (before the development of MOF) results in high economic costs, since it is impossible to reliably predict the further course of the disease; on the another hand, a start of renal replacement therapy in septic shock and detailed MOF picture has no organ protective effect and does not contribute to reduction of treatment cost [10].
The use of extracorporeal detoxification methods in the complex treatment of destructive pancreatitis complicat ed by sepsis and septic shock eliminates histotoxic hypoxia and is direced to prevent the development of MOF [11].
The research objective of the study was to evaluate the effectiveness of extracorporeal detoxification methods in the complex treatment of destructive pancreatitis.
The research tasks included: 1. Evaluation of the severity of endotoxemia in destructive pancreatitis.
2. Assessment of hemodynamic parameters in patients with destructive pancreatitis.
3. Assessment of the effectiveness of extracorporeal detoxification methods.
4. Determining the impact of a small volume infu sion therapy on the clinical picture of the disease.

Materials and Methods
The study enrolled 20 patients (40-53 years old) with destructive pancreatitis hospitalized in the Intensive care unit of CCH No. 4 in Almaty city.The cohort of examined patients includ ed 14 men (70%) and 6 women (30%).Nine patients (45%) were with hemorrhagic necrotizing pancreatitis, 7 (35%) patients had a fatty pancreatonecrosis, whereas mixed forms were found in 4 (20%) cases.The main causes of destructive pancreatitis were the following: dietary factor -35%, alcohol abuse -30%, cholelithia sis -15%, the cause has not been specified in 20%.-Most patients (75%) were admitted in 12-24 hours after the disease onset.
All the patients underwent complex clinic and laboratory and instrumental examination including the collection of anamnestic data, physical examination, evaluation of clinical and biochemical parameters, morphological studies following per formed surgery, as well as ultrasound at admission and on an every day base.
Ultrasonography was performed on the following devices: SonoAcePico (Korea), Vivid 7 (General Electrics, USA), Toshiba Xario (Japan).They determined the shape, contours, size of the pancreas as a whole and each of its departments, echogenicity, and the state of the pancreatic duct, the presence and the absence of parapancreatic infiltrates, abscesses, cysts, as well as the condition of the initial compartments of the small intestine (paresis, the pres ence of fluid in the lumen of the intestine with a random movement or sluggish antiperistalsis), hydrothorax, expansion of the retrogas tral space, etc. Evaluation of the incidence of ultrasound patterns was carried out three times (before 12 hours, from 12 untill 24 hours and more than 24 hours) from the time of the disease.
Criteria for enrollment into the study: 1) presence of severe sepsis / septic shock; 2) severity by APACHE II scale equals from 12 to 26 points; 3) assessment of the severity of MOF by SOFA scale equals from 12 to 21 points.
Depending on the nature of ongoing intensive care the patients were divided into 2 groups.
The severity by APACHE II scale in group 1 was estimated to be 24.2±1.2 points, in a group 2 it was 23.4±2.3points.The severity by SOFA scale was 12.3±0.1 points (group 1) and, 12.1±0.1 points (group 2).There were no differences between the groups in severity at admission to hospital.
Extracorporeal detoxification program in the patients with necrotizing form of pancreatitis in group 2 (control) included: 1) Surgical correction; 2) ILBI and UVI of blood in 3-4 hours after the surgical correction; 3) plasmapheresis was conducted in 6-8 hours after the surgery.
HDF and albumin dialysis were started in the period between the surgical interventions and in the 7th day of the treat ment in the resuscitation and intensive care unit, once a day, with a duration for 8-12 hours; 3-5 sessions of HDF and 1-2 sessions of albumin dialysis were performed.The main indications were worsening of the clinical condition, the growth of endogenous intoxication with aggravation of MOF that reflected the severity of sepsis.
The first HDF sessions and albumin dialysis started at least 6-8 hours after completion of the surgery.The vascular access was performed through Certofix DuoHF double barreled venous catheter.The blood flow rate through a hemodiafilter for hemody namically stable patients was established as 150-200 ml/min.In the patients who needed infusion of sympathomimetics the blood flow was 80-100 ml/min with a gradual gathering the speed and prolongation of detoxification session up to 12 hours.
GDF was performed by means of Multifiltrate apparatus using standard packaged sterile solutions on the basis of bicarbon ate buffer.Substitution in volume of 2000-4000 ml/h was carried out by predilution with AV600S hemodiafilters.The dialysis fluid flow was 2000-4000 ml/h.
Albumin dialysis was performed by means of MARS Monitor 1 TS apparatus combined with Multifiltrate apparatus.MARS flow section was filled with 600 ml of 20% albumin solution.Albumin perfusion rate was 150 ml/min.Anticoagulation was car ried out with heparin at a constant infusion of 8-10 U/kgoh under the control of coagulation parameters.Ultrafiltration rate was 50-150 ml/h.
The treatment was complemented by carrying out a discrete plasmapheresis by Haemonetics PCS 2 machine to remove anti gens, antibodies, biogenic amines, immune complexes, the decay products of tissue purulent inflammatory origin [5,8].
Discrete plasmapheresis was performed from the first day after surgery rehabilitation of the focus of infection and antibiotic therapy.Before the plasmapheresis hypoproteinemia, hypo glycemia, anemia, fluid and electrolyte abnormalities were cor rected.In unstable hemodynamics vasopressors were used (dofamine, mesaton etc.).Single volume of plasma exfusion was 600-1200 ml.Exfused plasma volume in patients of group 1 was filled up with donor fresh frozen plasma (40%), 10-20% solution of albumin (20%), colloid crystalloid solutions (40%).Depending on the initial severity of the condition, the effectiveness and toler ance of treatments 3-6 plasmapheresis sessions were performed every 24-48 hours.
Quantum therapy methods were employed in both groups according to the following procedure: -Intravenous laser blood irradiation (ILBI) -emission wavelength 635 nm, radiation power at the fiber end 1.5-2 mWt, exposure time was 20 min, within 7-10 days to decreasing the inflammatory responses and improving microcirculation.
-Ultraviolet irradiation (UVI) of blood was performed at wavelength of 365 nm, at radiation power at the fiber end of 1.0 mWt and exposure time of 5-7 min within 10 days to stimulate cellular and humoral immunity [4,6,9].
«Гемодинамический профиль» в обеих группах соответствовал гиподинамическому типу кровообраще ml/kg of the body weight), first by stream infusion, than by drop infusion.The main components of the drugs included sorbitol and sodium lactate.Both drug formulations contained electrolytes (sodium, potassium, calcium, magnesium) in a balanced ratio.Sodium lactate has a neutral reaction, however, when introduced into the bloodstream it dissociated to sodium ions and lactic acid metabolized in the liver to sodium bicarbonate that increased alkalinity of the blood.The correction of metabolic acidosis is then carried out gradually and did not cause sudden fluctuations of pH unlike the exposure of sodium bicarbonate.
Sorbitol ( С 6 Н 14 О 6 ), the hexabasic alcohol, that is quickly included in the overall metabolism, was employed for immediate energy needs, increasing the energy balance, strengthening the processes of regeneration of hepatocytes, and to ensure antiketo genic effect.Hypertensive (20%) sorbitol solution has high osmo larity and has diuretic effect, and 6% isotonic one has antiplatelet properties [12,13].
To evaluate the hemodynamic parameters the blood pressure (systolic, diastolic, mean), central venous pressure, heart rate and pulse were measured.Assessment of oxygen transport was carried out on the basis of gas and acid composition of the blood, pulse oximetry and capnography.
Blood samples were harvested on days 1, 3, 5, 7 before and after sessions of the extracorporeal detoxification during the patient' stay at the ICU.
Laboratory examination of the patients included routine blood and urine tests blood biochemistry (total protein, albumin, urea, creatinine, total, direct and indirect bilirubin, ALT, AST, glu cose, electrolytes, amylase, lactate) and status of the hemostasis system evaluation (PTI, fibrinogen).

Results and Discussion
The patients were admitted in severe and critical condition with a clinical picture of acute pancreatitis and intoxication, ultrasound of the abdomen confirmed destructive pancreatitis -an increased size of the pan creas, decreased echogenicity of the parenchyma, the for mation of foci of destruction, the appearance of the liquid in the peritoneal omental sac, formation of cysts.
Hemodynamic profile in both groups corresponded to hypodynamic type of blood circulation, which was caused by sepsis and hypovolemia related not only to the redistribution of the liquid, but also to its increased losses (perspiration, secretion into the gastrointestinal tract, etc.).Increases in heart rate, in some cases up to 150 per minute, were considered as an important element of com pensatory mechanism aimed to maintain a sufficient blood supply to organs and tissues.The hemodynamic stabiliza tion required large doses of sympathomimetics (dofamine 6-12 mcg/kg/min, mesaton 200-2000 mg/kg/min, adrenalin 200-2000 mg/kg/min).
Slightly elevated CVP as a result of the PTA was normalized on day 3. Thus, the extracorporeal detoxifica tion methods resulted in hemodynamic stabilization at an earlier date, this is due to the rapid elimination of cytokines, osmotic balance correction and prosthetics of homeostatic kidney function.There were no significant differences between groups in values of parameters of «red blood» and platelets.The level of white blood cells, leuko cyte index of intoxication and lymphocytes, stab and young forms of neutrophils was significantly reduced.
At the time of admission to the ICU the levels of white blood cells in both groups exceeded normal levels (from 9 to 16 10 9 /l).Decrease in white blood cells in group 1 to normal values (mean of 8.6±2.6) was observed on day 7.In group 2, the number of leucocytes remained elevated during the entire period of staying of patients in the ICU.Biochemical testing of blood revealed statistical ly significant changes in the level of protein, albumin, urea, creatinine, bilirubin, ALT, AST, amylase and lactate.
Within seven days the total protein in the blood of patients from both groups remained below normal values.On days 3-5 the amount of total protein in patients of group 1 was 10.3% higher compared to group 2. On day 7 an increased albuminuria (21.6% more than norm) was observed in group 1 compared to group 2 (Table 2).
On day 3 patients from group 1 experienced a decrease of total bilirubin by 46.2%, ALT -by 33.3%, AST -34.4%, urea -to normal values by 49.3%, creati nine -to normal values by 23.4%, amylases by 49% com pared to group 2 followed by normalization of values on day 7.At all stages of the study, blood glucose levels in both groups remained within the normal range, but in group 1 the blood glucose level was kept at a lower values correspondent to lowest limits of norm.In 3-5 days in group 1 fibrinogen levels decreased to normal values by 27.9% compared to group 2. By day 3 in group 1 an increase in platelet counts to normal values by 10.5% was noted compared with group 2.
On day 3 a decrease of the LII pattern by 59.2% was noted in a group 1 compared to group 2. It was revealed that early inclusion of methods of extracorporeal detoxifi cation in the complex treatment of pancreatic necrosis reduces the severity of endotoxemia in 2-3 postoperative days, in group 2 -only in 15 days (Table 3).
The analysis of the data showed that in group 1 lac tate level came back to norm in 7 days (mean 1.8±0.5 mmol/l), in group 2 -in 15 days (mean 1.7±0.2mmol/l).
It was found that early extracorporeal detoxifica tion in the complex treatment of pancreatic necrosis reduced clinical manifestations of endotoxemia in group 1 by 30-50% compared to group 2. Thus, patients in group 1 experienced a two fold decrease in APACHE II scoring and a decrease in the severity of endotoxemia in 2-3 postoperative days were observed, whereas in a group 2 the same changes were observed only on day 15 (Table 4).
Using the SOFA scaling the patients of group 2 remained longer in a critical condition resulted in higher mortality (41.1%), whereas in group 1 all patients survived (Table 5).

Conclusion
1. Eearly inclusion of extracorporal detoxification in a comprehensive treatment protocol of destructive pan creatitis reduces clinical signs of endotoxemia by 30 50%.
2. Hemodynamics in a destructive pancreatitis cor responds to a hypodynamic type of circulation caused by sepsis and reactions to hypovolemia.Extracorporeal detoxification resulted in hemodynamic stabilization at an earlier date presumably due to the rapid elimination of cytokines, osmotic balance correction and prosthetics of homeostatic kidney function.

of patients after the admittance to ICU at the stages of study, days
1 1 ; 3 70 w w w .r e a n i m a t o l o g y .c o m

Число больных в процентах, получавших инотропную поддержку. Table 1. Percent of patients receiving inotropic support during the study.
w w w .r e a n i m a t o l o g y .c o m
1 1 ; 3 72 w w w .r e a n i m a t o l o g y .c o m