Abstract
Introduction
Severe acute pancreatitis is still a difficult clinical
problem, it is a challenge for medical teams, which should include the strategy
of personalized medicine. In clinical observations, among patients with the
fulminating course of acute pancreatitis developed during the first hours
leading to irreversible multiorgan failure and death.
Aim
To evaluate the frequency of occurrence and analyze the
progression and treatment of severe acute pancreatitis (AP) in patients
hospitalized during the years 2004–2010 at the Clinical Surgery Ward.
Material and methods
One thousand and fifty patients treated for AP were included
in the study; 97 patients with severe AP were subjected to a detailed clinical
analysis.
Results
The average age of the patients was 52.8 years. Relapses
occurred in 14.9% of patients. The severe form of acute pancreatitis was
diagnosed in 97 patients, which accounts for 9.2% of all the illnesses, and occurred
significantly more often in male patients (p < 0.01). The most frequent
etiological factors were cholelithiasis (46.4%), and idiopathic pancreatitis
(27.8%); alcohol consumption was responsible for 22.7% of the cases; the
occurrence of both a bile-derivative and alcoholic factor was found in 3.1% of
the cases. A worsening clinical state resulted in laparotomy in 26 patients
(26.8%), and re-laparotomy in 5 patients. Necrosectomy was performed on 15
patients, of whom 33.3% died due to complications. The total mortality in
severe AP was 38.1%. The average age of the deceased was 66.5. Early deaths
within 14 days were noted in 78.4% of patients (n = 29) who died due to severe
AP.
Conclusions
Severe AP in spite of implementing modern diagnosis and
treatment methods is still associated with a high risk of death. Constant
clinical observation and use of available prognostic scales are essential in
improving AP prognoses.
Keywords: acute pancreatitis, etiology, treatment,
complications
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Introduction
Acute pancreatitis (AP) is an acute inflammatory process of
the gland itself, with progression to a greater or lesser degree of surrounding
tissue or remote organs. The epidemiological data from the last few years
indicate an increase in the frequency of occurrence of both acute and chronic
pancreatitis. High geographical variation can be observed globally in the
incidence of AP, ranging from 15.9/100,000 to 73.4/100,000 per year [1–4]. In
Poland there are no studies of prospective epidemiological data concerning the
incidence of pancreatitis. Data recently published for the Świętokrzyskie
Voivodeship indicate that in this region, AP affected 99.9/100,000 inhabitants.
First-time incidents in the analyzed period of one year affected 79/100,000
inhabitants [5]. In the recently published retrospective study of the
Trzebnicki district, the frequency of occurrence of AP in this area was
estimated at 64.4/100,000 cases per year, of which 42.3/100,000 per year were
first-time incidents [6]. Cholelithiasis and alcohol consumption, responsible
for 80% of AP incidence, are the dominant etiological factors [7, 8]. It should
be stressed that the so-called idiopathic or unexplained causes of AP are
usually of microlithiasis etiology [9]. Endoscopic retrograde cholangiopancreatography
(ERCP), hyperlipidemia, drugs taken by the patient, hyperparathyroidism,
sphincter of Oddi dysfunction, congenital defects, abdominal trauma, surgery,
viruses, bacteria, parasites, autoimmune-based illnesses, and cystic fibrosis
are among the less frequent causes [10]. In the majority of cases, AP has a
benign course, characterized by a slight dysfunction of the organ, which
regresses after conservative treatment. In about 20% of patients, the disease
has a severe course and may lead to life-threatening multi-organ failure. Local
and/or system-wide complications occur in the severe form of the disease.
General complications may affect the cardiovascular system, the respiratory
system, kidneys and disorders in hemostasis. Metabolic disorders, bleeding into
the alimentary canal, and complications from the central nervous system may
occur as well [11]. General mortality in AP is lower than 5%. In its severe
form, hospitalization is prolonged as a result of pancreatic necrosis and
multiple organ dysfunction, which leads to a much higher mortality rate [12].
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Aim
The aim of the undertaken research was to analyze the
clinical course of AP and therapeutic indications for conservative therapy and
surgical treatment in patients treated within the years 2004–2010 at the
Clinical Ward of General, Oncological and Endocrine Surgery of the Voivodeship
Hospital in Kielce. The results of the research in the selected aspects refer
to a group of hospitalized patients suffering from the benign form of AP.
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Material and methods
Subjects
One thousand and fifty patients treated for AP during the
years 2004–2010 at the Clinical Ward of General, Oncological and Endocrine
Surgery of the Voivodeship Hospital in Kielce were included in the research.
Between 3500 and 3700 patients are treated at the ward every year. The
inclusion criterion was clinical recognition of AP. All patients treated due to
AP in the analyzed period were included in the research. The final diagnosis
was based on medical history, clinical presentation, determination of α-amylase
activity in blood serum and urine and imaging examinations (ultrasonography
(USG), computed tomography (CT), nuclear magnetic resonance (NMR), chest X-ray,
or a plain film of the abdominal cavity). The criterion of qualifying for
further analysis was the recognition of severe AP, and consequently the
occurrence of one of the following factors: 1) local complications (necrosis,
false cyst, pancreatic abscess); 2) multiple organ dysfunction syndrome (MODS);
3) fulfillment of at least 3 criteria in the Ranson scale; 4) a result of 8
points or more in the APACHE II scale (Acute Physiology and Chronic Health
Evaluation II). In the group of 97 patients with severe AP, the following data
were included in the assessment: age, gender, cause and calculation of severity
of AP by means of the Ranson and APACHE scale, previous treatment methods,
complications, and mortality.
Statistical analysis
In the study of significance of the mean difference, the
parametric Student’s t-test was used. The significance of difference between
distributions was analyzed by means of the χ2 test. In some cases the
significance of difference between the indexes of structure was analyzed by means
of “z” statistics. The null hypothesis stating that there was no significant
difference was tested each time. The basis for possible rejection of the zero
hypothesis, or stating that there was no reason for rejecting it, was a
comparison between the value p, achieved in the test procedure, and a specified
significance level of the test α = 0.05 (if p < α, we reject the null
hypothesis). The significance of difference in the women’s ages was determined
by means of the Z-test for the whole of the examined group (n = 1,050).
Interval estimation of the unknown age mean value for the whole population (the
confidence coefficient 1 – α = 0.95 was assumed). For some variables, instead
of using the parametric Student’s t test, one of the most effective nonparametric
equivalents, the Mann-Whitney U-test, was used. The reason for selecting this
test was that the consistency condition of a normal distribution (Gaussian
distribution) for these quantitative variables (the consistency with normal
distribution was analyzed by means of the Shapiro-Wilk test) was not fulfilled.
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Results
During the years 2004–2010, 1,050 cases of hospitalization
for AP were registered at the Clinical Ward of General, Oncological and
Endocrine Surgery of the Voivodeship Hospital in Kielce (final recognition
K-85). There were 416 women and 634 men in the group. The average age of the
patients was 52.8 years (the median was 51 years). The women hospitalized for
AP were older than the men (the average was 61.1 years vs. 47.4 years; standard
deviation was 17.8 and 15.8 respectively). During the 7-year period of the
study, relapses of AP occurred in 14.9% of the patients (4.8% were female
patients and 10.1% were male patients). Among this group, 57.7% of the patients
were admitted to the hospital for a period of time shorter than 2 months before
they became ill. A relapse was defined as another admission to the hospital
without ascribing any time framework. Most patients with relapsing AP were
readmitted to the hospital once (62.8%), 19.2% of patients were hospitalized
two more times, several people were admitted to the Surgical Ward more than
three times, and one person was treated fourteen times. According to the
classification from Atlanta, the Ranson and APACHE scale, the severe form of AP
was diagnosed in 97 patients, which accounted for 9.2% of total AP cases. The
severe form of AP occurred significantly more often in male patients (p <
0.005). The median age of the women was higher than that of the men (70 years
vs. 49.5 years), but there was no statistical significance (Table I).
Table I
Table I
Characteristics of the group of examined patients with
severe acute pancreatitis
The most frequent etiological factor of severe AP was
cholecystolithiasis, in 46.4% of patients (80.6% of females and 30.3% of
males), alcohol was the cause of the illness in 22.7% of patients (28.8% of
males and 9.7% of females), while both cholelithic and alcoholic factors were
the cause in 3.1% of the patients (4.5% of males). An etiological factor was
not recognized explicitly in 27.8% of cases (9.7% of females and 36.4% of
males). In these cases, the most probable cause of severe AP was cholelithic
etiology with the presence of micro-cholelithiasis. The average time of
hospitalization for patients with severe AP was 25 days (minimum 1 day, maximum
128 days, median 19 days). In order to assess the degree of involvement of a
disease and prognosis of complications and mortality the Ranson scale and
APACHE II (the Acute Physiology and Chronic Health Evaluation) scale were used;
the assessment was performed during the first 24 h of the patient’s stay at the
ward. The average score in the Ranson scale was 2.1 (minimum – 0 points,
maximum – 4 points, median – 2 points, standard deviation – 0.99), while in the
group of patients who died it was 2.6 points. According to the APACHE scale the
average score in the examined group was 11 points (minimum – 0 points, maximum
– 34 points, standard deviation – 6.6 points). The average score in the APACHE
II scale in the group of patients who died was higher than in the others (14
points vs. 11 points). During the first 24 h of hospitalization an ultrasound
examination of the abdominal cavity was performed. Computed tomography (CT),
which depended on clinical indication, was performed no earlier than 72 h after
clinical symptoms appeared. The degree of morphological complications occurring
in AP was determined by use of the computed tomography severity index (CTSI)
drawn up by Balthazar et al. (Table II).
Table II
Table II
Complications of severe acute pancreatitis
Vital signs were monitored in patients with severe AP, and
positive fluid balance and analgesic treatment were applied. Carbapenems were
used for protection against infection. In justified cases, targeted antibiotic
therapy was used based on transdermal/transcutaneous biopsy or intrasurgical
material. Antibiotics were used from 7 to 14 days. An intestinal and/or
parenteral nutrition diet was begun after the assessment of the clinical state
between the third and the fifth 24-hour period of hospitalization. Within the
analyzed cases, combined nutrition – parenteral and periodic intestinal feeding
– was used in 80 patients, and only intestinal feeding was used in 17 patients.
Early performance of endoscopic retrograde cholangiopancreatography (ERCP) (3
patients) was the method of treatment of acute biliary pancreatitis with
symptoms of jaundice and cholangitis. After achieving improvement of the
clinical state, usually after 4 to 8 weeks, a cholecystectomy was performed.
Deterioration in clinical state was the reason for laparotomy in 26 patients
(26.8%), and relaparotomy in 5 patients due to complications. The indication
for laparotomy was infected necrosis with symptoms of sepsis (19 patients),
diffuse peritonitis (5 patients), or bleeding into a pancreatic fluid cistern
(2 patients). Necrosectomy with irrigation drainage was performed in 15
patients, including 5 patients (33.3%) who died after the procedure due to
complications. One patient underwent cystogastrostomy in the late period of
hospitalization. Laparotomy with different forms of closed drainage was
performed in other patients. Among the registered complications after surgery
in patients who underwent laparotomy, the most frequently observed
complications were: infection of the wound (7 out of 26 patients; 26.9%),
enterocutaneous fistula in 3 patients (11.5%), bleeding from the peritoneal
cavity in 3 patients (11.5%), hernia in 2 cases (7.7%), and bleeding from the
gastrointestinal tract in 4 patients (15.4%) (Table III).
Table III
Table III
Complications after surgery
In spite of implementing intensive treatment, 22 patients
(22.7%) required transfer to the intensive care unit because of the following
complications: acute respiratory distress syndrome (ARDS) in 27 persons, acute
renal failure (25), circulatory insufficiency (34), hepatic failure (15),
multiorgan failure (30), and sepsis associated delirium (SAD – 14 patients).
The total mortality in the group of patients who suffered from severe AP was
38.1% (37 patients). Among those who died the number who suffered from acute
biliary pancreatitis dominated (21 people; 56.8%), but the etiology was not
explained in 8 cases. The average age of the deceased was 66.5 years; the
standard deviation was 18.7 (the average age of the others was 51 years; the
standard deviation was 16.6). The influence of age on the frequency of deaths
was determined to be (p < 0.0001). The patients died most frequently during
the first 3 days after their admission to hospital (20 people), while 9 more
patients died within 14 days. Early deaths were defined as deaths occurring
within 14 day after admission, and late deaths were defined as deaths occurring
more than 14 day after admission. Early deaths, within the first 14
twenty-four-hour periods of hospitalization, were registered in total in 29
patients (78.4%), who died from severe AP. Among this group of deceased
patients, 7 were treated with an open abdomen technique, and 5 people died
within 3 days after being admitted to hospital (Table IV).
Table IV
Table IV
Characteristics of early and late deaths in severe acute
pancreatitis
For analyzing significant differences between the
distribution of the variable “age” of the population of early and late deaths
and for the mean values for the Ranson scale, the non-parametric Mann-Whitney
U-test was used. The Student’s t-test was used for analyzing the significance
of differences for the average of the “APACHE II scale” parameter. The
significance of differences between the distributions of the population of
early deaths and the population of late deaths for both gender and etiology
reasons was analyzed using a χ2 test. The presence of infectious and aseptic
necrosis was treated and tested as an index of the structure of the population
of early and late deaths (Z-statistics were used). The p values showed that
there was a reason for rejecting the null hypothesis (about equality of means,
distributions, and indexes of structure) only when the APACHE II scale is taken
into consideration. Here the null hypothesis was rejected at the significance
level α < 0.05.
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Discussion
Epidemiological data from different countries indicate that
there is an increase in the number of patients suffering from AP. An analysis
of hospitalizations between 2004 and 2010 indicated that the number of hospital
admissions remained at the level of 150 yearly. The average age of the admitted
patients was comparable with the tendency for higher incidence in older women
than men, which was presented in the academic literature [10, 13, 14]. The
confirmed frequency of relapses (14.9%) was lower than those reported in other
studies [15]. Cholecystolithiasis was the most frequent etiological factor and
alcohol the second. Endoscopic retrograde cholangiopancreatography may be the
rarest cause of AP. In recently published research from our centre, AP after performing
was recognized in 2.6% of the patients [16]. The general death rate due to AP,
which was 3.7% in a group of 1,050 patients, was comparable with data from the
academic literature [10, 14]. Age is depicted in the academic literature as a
factor which increases mortality significantly [1, 14, 17, 18]. Such a tendency
was also observed in our work but the statistical significance was not
confirmed. Despite the development of medical science, a severe form of AP is
still a big clinical problem with high risk of complications and a high death
rate. Severe AP was recognized in 9.2% of the patients suffering from AP. Data
from the academic literature indicate frequency of 15–20% of the severe forms
of AP. The initial assessment of the severity of a disease has great prognostic
importance. Markers of pancreatitis and/or markers of acute pancreatic necrosis
are indicated among the isolated prognostic coefficients. The correlation of
the level of procalcitonin with the presence of infection with acute pancreatic
necrosis and multi-organ failure is being sought [19]. Other research indicates
the usefulness of analyzing the level of D-dimer, protein S and protein C
between the first and third 24 h of a disease in prognostication of the course
of AP [20–22]. However, because it is admitted that isolated prognostic factors
are not effective in predicting complications, the recommended prognostic
Ranson and APACHE II scales were used in the center of the authors of this
work. Such an approach also has its limitations, because the results of the
study show that severe course of disease was predicted using the Ranson scale
for only one third of the patients. Using the APACHE II scale turned out to be
more efficient in predicting disease severity. 54.6% of the patients who suffered
from severe AP were given values ≥ 8. The lack of possibility for taking into
consideration the passing of time from the moment of the occurrence of symptoms
until the time of hospitalization may have an influence on such a result, which
was suggested in the studies conducted earlier [18].
The average score in the APACHE II scale in the group of
patients who died was lower than in Gotzinger’s research (14 points vs. 21
points) [23]. Using the APACHE II scale increased the opportunity of forecasting
early deaths in a statistically significant way, which was also confirmed in
other studies [24]. One needs to take into consideration that the APACHE II
scale used during the day of admission to the hospital may become unreliable in
diagnosing acute pancreatic necrosis [11, 25]. Treatment of the patients with
severe AP was based on clinical indications, and included positive fluid
balance and early enteral and parenteral nutrition. The most recent studies
show a positive effect of administering fluid therapy with the use of mainly
crystalloids in the first hours of hospitalization [26]. Early enteral
nutrition can have an influence on the limitation of hypermetabolism due to the
developing systemic inflammatory reaction and can limit the occurrence of organ
failure as well as cutting down the time of hospitalization [27].
The indications for surgery in AP have changed in recent
years. In 2002 the International Association of Pancreatology worked out
guidelines concerning surgical treatment of AP, from which it results that
infectious necrosis with symptoms of sepsis is a valid reason for surgical
intervention and radiological drainage. A surgical procedure needs to be taken
into consideration no earlier than 14 days after the beginning of the disease
unless there are reasons for earlier intervention [28]. Emphasis is placed on
maintenance treatment and prevention of infection of necrosis and other
complications. Minimally invasive surgical and endoscopic necrosectomy is
performed in necessary cases [29].
In studies comparing the effects of early and late surgical
intervention, it was shown that mortality rate was lowered among patients for
whom late exploration of the abdominal cavity was performed. Generally, the
mortality rate among patients with severe AP decreased from 39% to 12% [30]. In
another study it was shown that the mortality rate was lowered among the
patients for whom the operation was performed 29 days after the beginning of
the disease in comparison with those patients who underwent the operation
between the 1st and 14th days (8% vs. 75%) [31]. In the analyzed material, the
postoperative mortality rate was high at 33.3% in comparison with the academic
literature: 16.3% [18], 18% [32], and 36% [31]. In our material, 5 patients who
were operated on died during the first 3 days of their stay in hospital.
The dynamics of the course of the severe form is sometimes
diversified. Systemic inflammatory response syndrome (SIRS) with accompanying
multiorgan failure becomes a cause of early death in the first 24 h of
hospitalization. Even intensive shock-controlling treatment, kidney replacement
therapy, and respirotherapy in respiratory failure may be largely ineffective
for some of the cases of the severe form. The mortality rate in the severe form
may reach 20%, increasing to 25% in infectious necrosis and to 50% in organ
failure [10, 33, 34]. In the studies of five European countries, the overall
mortality was 7.8%, but in the necrotic form was 16.1% [34]. In the analyzed
material the mortality rate in the severe form of AP was higher than that
presented in the academic literature and reached 38.1%. Such a high death rate
was caused by early deaths resulting from an incredibly quick and dramatic
course of severe AP. The high percentage of registered deaths caused by severe
AP was partly connected with more frequent hospital admission of patients in
poor general condition who were handed over from other hospitals of the
Voivodeship to a clinical ward. The consumption of very large amounts of
alcohol by patients who died also had a significant influence on mortality. A
higher death rate was registered for the lithiasic etiology of severe AP: 56.8%
of all the causes. A connection between etiology and gender, and frequency of
the occurrence of early and late deaths was not found. In research from Taiwan,
more frequent occurrence of early deaths from an alcoholic etiology and late
deaths from lithiasic etiology were reported [18].
In clinical observations, among patients with the
fulminating course of AP, severe toxemia developed during the first hours,
leading to irreversible multiorgan failure and death. Early development of
renal failure, shock and hepatic failure were observed as causes of early death
with fulminating AP [24]. Taking the most aggressive methods of treatment
against acute respiratory distress syndrome (ARDS), ventilation, acute renal
failure (hemodialysis), applying pressor amines (noradrenaline, dopamine),
antibiotic therapy, and fluid therapy may be ineffective and lead to the
patient’s death. The severe forms of AP of a diverse course often present as
acute pancreatic necrosis of varying severity and affect peripancreatic tissues
and retroperitoneal phlegmon. Such a state of the disease creates a temporary
opportunity to consider different methods of treatment:
cholangiopancreatography, sphincterotomy, drainage, necrotomy, irrigation
drainage, and possible repetition of laparotomy. The continuation of intensive
preventive treatment, struggle with sepsis, acute renal failure, thrombotic and
embolic as well as circulatory complications, connected with intervention
methods, may provide a chance to save the patient’s life.
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Conclusions
Despite implementing modern methods of diagnosis and
treatment, the severe form of AP still involves a high risk of death. In
clinical practice we meet patients with a fulminating course of AP, which leads
to irreversible organ failure, and the death of a patient during the first
days. In prognosis of the course of AP, constant clinical observation is valid
and it is also important to make use of the accessible prognostic scales, from
which the APACHE II scale turned out to be the most useful. Its use
significantly increased the possibility of predicting early deaths. Early
surgical treatment is connected with a high risk of complications and
mortality.
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