Have changes in the management of treatment of the patients with acute pancreatitis brought the expected result?

Summary

Introduction:
The severe acute pancreatitis (AP) remarked during the last decades the decrease of mortality to 10 – 20%. But many questions of the treatment of this disease are still opened.

Aim:
To add own experiences gained by the treatment of the group of patients at workplace of the authors, to the most actual professional literature which solves the abovementioned problem.

Patients and methods:
Being affected by the news published in professional literature and under the circumstances at own workplace, the decision to change the management of the treatment of AP has been made. The management referred to the enteral nutrition, epidural analgesia , antibiotic prophylaxy, pushing the surgical operation to the later period in the case of infected necrosis.

Comparing of two groups of patients - A (2003-2005 years) and B (2006-2008 years ) the authors came to the interesting results.

Results:
Applying the new protocol we noticed: Increase of percentage of patients with sterile necrosis from 46% to 58% , decrease of number of surgical re-operated patients from 43% to 33% and decrease of mortality from 53,8% to 18%.

Conclusion:
Applying the change of the management of treatment of the patients with the complicated form of acute pancreatitis, the authors achieved remarkable results. Nevertheless, these results have to be evaluated very cautiously, because of not too large group of patients, who have been treated.

Key words:
complicated acute pancreatitis, change of the management

Introduction:

Acute pancreatitis (AP) is a disease, which with its various clinical forms from mild to the most severe with serious complications that attempt the life of a patient.

According to the Atlanta classification the severe AP occurs approximately at 25% of all patients with AP and it is associated with 10-20% of mortality. Death of the AP patients is often connected with failure of at least one organ.

There are two phases of the severe AP relating to the mortality. The first phase is characterized by the hypovolaemia or even by the shock. It is accompanied by the systemic inflammatory responsive syndrome (SIRS) with production of inflammatory mediators and cytokinins, which cause consecutive injury of lungs, livers and cardiovascular system. The multi organ failure is a very common appearance in the case of the severe AP patients and it happens very often even when the infection is absent.

The second phase of this disease (end of 2.week) is characterized by the complications caused by the infection of pancreatic necrosis. About 40-70% patients with necrotic AP is afflicted by the infection of the pancreatic necrosis, which causes the death of AP patients (4).

The extent of the pancreatic necrosis and the duration of disease are the risk factors of the local pancreatic infection. Its incidence tends to culminate in 3.week of disease, though it may appear in whichever phase of the disease (11). Severe AP requires treatment at the hospital, which is developed from the personal, professional and technical point of view, where is a possibility to do the full diagnosis and therapy and the inter divisional cooperation, what is the basic presumption for treatment and diagnosis of AP.

Beside full intensive treatment of AP there is a non changeable role of the surgical - operational treatment. Some indications for surgical treatment are no doubtful, some of them are the subject of discussion. The documented persist infected necrosis and abscess is clear indication for the surgical treatment. Permanent acute abdomen, especially so called IAC (intra abdominal compartment syndrome) and persistent or increasing local complications (bleeding, ileus, bleeding of GUT, vascular ileus and others) are also the definite indication of the surgical intervention. Many authors consider the sterile necrosis, which causes the multi organ failure and which does not react to the maximal intensive treatment more than 72 hours, as an indicator of the surgical treatment (22).

The changes in the management of the patients with severe AP in the last decade contributed to the decrease of mortality. The aim of this study is to show the progress in the management of the patients with severe AP, comparing two clinical groups of patients.

Clinical group of patients and the methods:

All patients who were hospitalized due to the AP symptoms in the period from January 1^st 2003 to December 31^st 2008 at the I. surgical clinic in Košice, were included to this study. Those patients, who were primarily hospitalized and treated at other workplaces and were moved to our institute during their disease, were excluded from this study.

The total number of the patients with AP during onset symptoms was 258 ones. All patients were hospitalized at the Intensive Care Unit, they received the standard intensive care (palliation of pain, nasal gastric tube, central vein catheter, urinary bladder catheter, intensive monitoring of the basic vital functions, intensive rehydration treatment, giving the inhibitors of proton pump, low molecular weight heparin, giving the prophylactic antibiotic therapy).

In the case of biliary AP, mainly joined with jaundice, cholangoitis or USG suspicion for the presence of the stones in common bile duct, the patients were underwent urgent ERCP procedure during the first 48 hours after onset AP.

The distinguishing of the mild forms and severe forms of AP were carried out using Ranson criteria, APACHE score, the daily follow up of level of CRP and measurement of percentage of involvement of pancreatic tissue by CT severity index ( Balthazar CT scoring system).

The first CT examination was carried out first time after 48 hours from the beginning of disease. The diagnosis of the infected necrosis we did according to the clinical finding, inflammatory markers (white blood cells, CRP, procalcitonin), USG and CT finding (presence of gas bubbles).

Patients with MOF were moved from the Intensive Care Unit to be hospitalized at Clinic of anesthesiology and intensive medicine of our institute.

The clinical group of hospitalized patients was divided into 2 subgroups. Group A included the patients hospitalized from January 1^st 2003 to December 31^st 2005. This group was evaluated retrospectively. The second Group B included the patients hospitalized from January 1^st 2006 to December 31^st 2008. This group was studied prospectively, according to the clinical protocol prepared in advance, which reflected the changes in management of the patients with the severe AP after confirmation of necrosis.

These changes include:

• enteral nutrition fed by the three-luminal tube (TLT) applied by fibroscope, checking the position by the contrast X-ray exam or by enteral nutrition through jejunostomy, in the case of already operated patients. Enteral nutrition was applied after the signs of the cardiovascular instability has disappeared. We used the enteral nutrition enriched of the glutamine, arginine and omega-3 fatty acids and fibres. The dose was gradually increased from 20 ml/hour to 1000 ml/24hours.
• the second change includes an application of the epidural catheter to palliate the pain and to recovery of intestinal peristalty.
• the continual measurement of the intra abdominal pressure with the catheter in urinary bladder
• the changes in the prophylactic application of antibiotics (III. generation cephalosporins which were administered in Group A were replaced in Group B by imipenem. In both groups the prophylactic application lasted maximum 14 days).
• Necrosectomy was indicated and performed as late as possible, usually the surgical procedure was pushed to the 3rd or 4th week of hospitalization.

Results:

Table No. 1 shows the basic characteristic of both subgroups A and B. It follows less frequency in Group A, however the male / female ratio and the occurrence of the necrotic AP was similar. The percentage of the patients with necrotic pancreas and the patients, who needed ERCP procedure, was similar as well.

Further we will be concerned only with the patients with severe (necrotic) AP.

Table No. 2 shows the characteristic of the patients with severe AP. In both groups there is a dominance of male and the similar average age, Ranson score, as well as a number of patients with necrotic pancreas over 30%. Alcoholic etiology occurred more often in Group A. Also we noticed the higher number of patients, who needed hospitalization at Clinic of anesthesiology and intensive medicine.

During the hospitalization, mainly during the period from 72 hours to 7th day, we provided intensive treatment in both group, however in some cases in spite of our intensive effort, the multi organ failure occurred. In the case of presence of abdominal compartment syndrome, we indicated the surgical intervention including intra abdominal decompression.

Presence of the infected pancreatic necrosis or abscess was a clear indication for surgical intervention. Individual indications and the timing of the surgery is presented in the Table No. 3. In Group A, it shows more often indications to the surgical solution in the first days and weeks of hospitalization period. Comparing Group B, mainly in the case of infected necrosis, the surgical operations were pushed to the third or forth week. This was reflected also in the mortality of operated patients, when we recorded 71% of mortality in Group A and 25% of mortality in Group B. The types of surgical procedures shown in the Table No. 4.

While during the first days we performed only the surgical revision and drainage or open abdomen, in the case of infected necrosis we preferred necrosectomy with closed continuous lavage. The table also shows the number of patients with reoperations in both groups, which are less frequent in Group B.

Comparison of the mortality in both groups is presented in the Table No. 5. It shows less mortality in Group B (18%) and also the higher number of patients with non infected necrosis (17 = 58%) than in Group A (6=46%).

Comparison of the causes of death in both groups is presented in the Table No. 6. While only 2 patients dead for the pancreatic sepsis with multi organ failure, the remainder 10 patients dead for MOF in first 10 days after the hospitalization.

Discussion:

Despite of the long lasting dissatisfaction with the mortality level of the patients with severe AP, nevertheless during last decades as a consequence of the positive shift in diagnostic methods and treatment of AP, we succeeded to decrease mortality of severe AP patients to 10-20% (17).

During the last 15 years a big step was done towards the understanding and development of AP and at the same time the great progress in the screening methods of pancreas (39).

In line with the other authors opinions (1), taking into account own experiences, we are convinced that the decrease of the mortality was caused by an early recognition of the severe AP and setting up the prompt and appropriate treatment, by the improvement of the nutritional support, early ERCP supplied to the accurately indicated patients, and using the effective antibiotic treatment.

The International Association of Pancreatology (IAP) proposed for AP treatment 11 recommendations (35, 39), which created the framework for contemporary management of AP. These recommendations are based on the principles of evidence based medicine. However, in many points, the need of further comparative studies was observed.

Positive trend of the decreasing mortality in the cases of severe AP was visible also at our workplace. These results have been already published previously (6, 7, 8). During the period from 2003 to 2005 the results overall got worse, when the mortality level of severe AP increased to 53.8%. After in-depth analysis of the causes of this negative result, the decision to change the management of the patients with AP was made. The new protocol was designed, which contained the change of the management, described in the above part Clinical group and the methods.

The contemporary standard of management of AP is the intensive conservative treatment with possibility of the diagnosis of its complications in the course of the therapy (28).

Very important part of the AP treatment is early and adequate fluid resuscitation during the first hours after admission in the case of patients with cardiovascular instability. When diagnosis of AP is confirmed, the treatment in line with a new protocol was applied.

Many reports were published about the positive influence of the early enteral nutrition in the case of severe AP. Cao with co-workers (12) published the results of meta analysis, which compared the results achieved by the enteral nutrition and total parenteral nutrition in the case of severe AP. Patients with enteral nutrition shown less risk of infection, less percentage of pancreatic and peripancreatic necrosis, as well as less overall complications, less often multi organ failure and low mortality.

Application of the three-luminal tube (TLT) with help of fibroscope was carried out in our Group B by own co-workers, who had enough experiences and owned endoscopy certificate. The application of the gastric aspirate and the enteral nutrition was tolerated well by all patients. Some of them perceived the abdominal discomfort and the slight increasing of the intra abdominal pressure. In these cases we have temporarily reduced the volume of the enteral nutrition.

The aim of the prophylactic application of antibiotics is to protect the sterile necrotic tissue against the development of infection.

In general, it is accepted, that 40-70% necrosis is infected. With regard to the high percentage of the infection of pancreatic necrosis and with regard to the fact that mortality is higher in the case of infected necrosis than in the case of sterile ones, the preventive application of antibiotics became the logical solution in the past. Now, there are controversial views on antibiotic prevention, which has to avoid the infection of the necrosis. The reason is except an unproved benefit from prevention also its possible risks (antibiotic resistance and development of mycotic superinfection from antibiotics) (16, 19, 29).

At present, the routine application of the prophylactic antibiotics to the patients with proven necrosis, has many supporters (16, 39, 31, 33 and 40). The conclusions of their studies show, that antibiotic prevention reduces the sepsis and mortality.

The recommendations in IAP reports (35, 39) say: „Prophylactic application of broad-spectrum antibiotics reduces infection of CT confirmed necrotic AP, but it does not improve survival“.

When choosing the antibiotics, it is pointed at the best results (decrease of necrosis, less necessities to surgical treatment, lower mortality (Imipenem or Meropenem) (13). Comparing Imipenem and Meropenem, no differences in incidence of the septic complications were observed. (26). Preventive antibiotics have to be administered during 7-14 days. Longer application than 14 days is not recommended (29).

Regarding the different opinions on the antibiotic prophylaxy, it is necessary to take into account the extent of necrosis of the pancreas. If the damage is less than 30% of pancreas parenchyma, the risk of infection is small (29).

Despite of all contra versions, many, also prestigious workplaces, at present administer the antibiotic prophylaxy in the case of severe AP, bearing the risk of contra productive effect. We assigned our workplace to this group.

In the cases of patients with severe AP, it is necessary from the beginning or during the treatment, in spite of the intensive conservative one, to consider the indication of the surgical treatment. During the initial phase after admission of patient with AP the situations appear, when in spite of the precise differential diagnostics (based on anamnesis, clinical examination, laboratory tests, USG) these does not bring the clear breaking up and the indication of diagnostic laparotomy can be actual. CT examination can be very helpful in such situations and it can decrease these doubts to minimum. Despite of the risk of laparotomy, the published opinions say, that it is less probable, that the diagnostic laparotomy exacerbated local inflaming process, though it can increase the risk of infection of pancreatic necrosis. This risk should be reevaluated in situation, when there is no other alternative approach in treatment without surgical intervention (20).

The indications for surgery which are also now discussed are the patients with sterile pancreatic necrosis and multi organ failure, which are non-responsible to the intensive treatment more than 72 hours.

In the literature, there is a published opinion (18), that patients with high extent of pancreatic necrosis with persistent multi organ failure, in spite of maximum intensive care, can have a benefit from surgery. The clinical status has to be revaluated daily, because the right timing of surgical intervention is very important. Intensive care is suitable until the indications for surgical solution are not fulfilled (22).

In our group we indicated the surgical solution in such situations in 7 days after admission to 7 patients. In this group we recorded 86% mortality (in Group A 100%, in Group B 67%).

Some authors recommend surgical solutions to the patients with sterile necrosis, whose status is not improved during 4 weeks of intensive care (24).

A right timing of necrosectomy is discussed up till now. Those, who propose an early surgery say, that patient benefits from the early removal of the tissue necrosis, as it results to the decreasing of the multisystem complications linked with the releasing of enzymes and toxic substantions. In the past, an early surgical intervention was preferred especially in the cases of system functions damage, but it resulted to the high mortality (22).

Götzinger study (22) pointed at the fact, that a benefit from the delay of the surgical intervention is in the enclosure of demarcation process of dead tissue. This demarcation enables the safe and sufficient following debridement, which leads to the successful surgical control of the pancreatic necrosis in one or more steps. The analysis of the timing showed, that necrosectomy performed after 3 weeks from the beginning of illness is linked with higher percentage of success of debridement of pancreatic necrosis, what resulted to the lower number of reoperations and lower mortality. Very early debridement (up to first 3 weeks) means an oversize percentage of mortality.

In rare situations, also IAH – intra-abdominal hypertension is an indication to decompressive laparotomy (21,37). IAH is caused by paralytic ileus, by large inflamation of retroperitoneal tissue, increased vascular permeability and also by liquid collections in abdominal cavity. It can be caused also by aggressive liquid hyper resuscitation (20).

Intra-abdominal hypertension is typical at the beginning of illness and can lead to the intra abdominal compartment syndrome (the intra-abdominal pressure is higher than 20 mm Hg), which can make worth organ dysfunctions.

At present some indications to surgical treatment are apparent and clear. The absolute indications to the urgent surgery are necrosis and pancreatic or peripancreatic abscess.

Infected necrosis begins at 40-50% patients with necrotic AP (25).

Infected necrosis means the necrotic area with bacterial contamination in devitalized tissue. Necrosis of pancreas and peripancreatic tissue is the risky environment for bacterial contamination.

The risk of pancreatic infection grows with the volume of devitalized tissue. It culminates in the third week from the beginning of the illness. But 25% of patients have the infection during first 7 days (20).

Although AP is at the beginning a sterile inflammatory disease, which leads to MODS, so the clinical features are difficult to distinguish from severe sepsis. The confirmation of presence of infection is when gas bubbles are found on the CT examination, also by the positive cultivation of specimen obtained from the necrosis by thin-needle technique. This technique is save and 90% precise (36).

Bacterial translocation from intestinal lumen (transmurally, by lymphatic and vascular way, by ascites) is the main mechanism of the infection transfer to the necrosis during the first weeks of the disease.

The microbiological examinations show that the origin of infection of pancreas is first of all the intestinal infections. Later sources are nosocomial infections of staphylococcus and enterococcus, including the multiresistant microorganisms and mycotic infections (11).

At present, the accepted opinion is that necrosectomy has to be done as soon as the evidence of the infected necrosis is confirmed (28).

The approaches of the surgical treatment of necrotic AP have been developed. Some of them are obsolete (resection methods), but various techniques of the necrosectomy of pancreatic and peripancreatic necrosis remain as dominant approach done by the classic laparotomy, by laparoscopic retroperitoneal miniinvasive surgery or percutaneous necrosectomy.

Additional techniques (after necrosectomy) are based on knowledge, that during surgical intervention it is not possible to remove all necrosis, because demarcation is not complete and too radical removal of this necrosis causes rather damage than benefit. On the other hand the rest of the necrosis can be a source of the persistent sepsis.

From the range of additional techniques may be mentioned the conventional surgical drainage with closing of the abdominal cavity and with location of the gravity or suck tube drains, open abdomen techniques also called laparostomy and at last the closed continuous lavage. It is possible to combine the abovementioned additional techniques.

We have own experiences with all additional techniques at our clinic and they have been published already (6, 7, 8). At present we use all of them, but we prefer the closed continuous lavage technique of bursa omentalis and retroperitoneum, as we published in 2003 (8), accepting also results of comparative studies (5, 9).

Delay of the necrosectomy to the 3rd- 4th week of hospitalization with applying the closed continuous lavage we obtained very good results in number of postoperative local complications as well as in the need of reoperations and no mortality in this subgroup of patients.

During last years many works were published about retroperitoneal necrosectomy (14. 34), laparoscopic assisted percutaneous drainage of infected necrosis and peripancreatic abscess (27), laparoscopic necrosectomy (15, 32. 38). Also other authors published the report about very positive results with percutaneous necrosectomy (10, 23). The benefit of percutaneous necrosectomy is mini invasive approach, which does not require total anesthesis, but the disadvantages are: longer time of hospitalization, higher doses of X-ray because of repetitive CT controls and high percentage of cases, when patients had to be underwent of laparotomy due to the insufficiency of previous one.

Pancreatic abscess contrary to the infected necrosis is well demarcated collection of purulent liquid without solid necrotic material. It is a result of infection, which arises from accumulation of liquid collections or from the area of necrosis, which has liquidized in the meantime. Comparing with the infected necrosis, the pancreatic abscess appears later (more than 4 weeks from the beginning of a disease) and the prolonged process is typical for it (18). If the pancreatic abscess contains small, solids particles, very often it is not suitable to drain it in percutaneous or endoscopic way (2, 13).

The other indication for surgery is the course of severe AP is bleeding. The intensive inflamation, large regional necrosis and secondary infection cause arouses of great vessels and cause pseudoaneurysm, which rupture may cause massive haemorrhagy to GUT, retroperitoneum or abdominal cavity.

The early diagnosis and following intervention radiology and surgical treatment are necessary for bleeding control. Debridement of the infected necrosis is the effective management for minimizing the risk of recurrent bleeding.

Fortunately the incidence of the hemorrhagic complications of severe AP decreases due to early recognition and intensive treatment of these patients (28).

Conclusion

Despite the mortality of severe AP decreased after the implementation of new diagnostic and medical procedures in last two decades, many questions are still open. The newest published studies and our own experiences changed our approaches to management of AP at our clinic and we have implemented a new protocol for treatment of patients with the severe AP.

The comparison of two groups of patients in three year period shown the positive results of new management of AP : increasing number of patients with sterile necrosis (58%), decreasing number of reoperations (33%) and decreasing level of mortality of severe AP to 18%.

Our answer to the question raised in the heading of this study is : YES, but we expected little bit better results.

However our clinical groups were relatively small, therefore our results are limited and we evaluate them as preliminary.

Adresa na korešpondenciu:
Prof. MUDr. Juraj Bober, CSc.
I. chirurgická klinika LF UPJŠ a FN LP
Trieda SNP 1
040 66 Košice
Tel.č.: 055 / 640 3893
Fax: 055 / 640 3808
E-mail: juraj.bober@upjs.sk