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Effects of time interval for hemofiltration on the prognosis of severe acute pancreatitis
En-Qiang Mao, Yao-Qing Tang, Sheng-Dao Zhang
En-Qiang Mao, Yao-Qing Tang,
Sheng-Dao Zhang, Department of Surgery,
Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025, China
Correspondence to:
En-Qiang Mao, Department of Surgery, Ruijin Hospital, Shanghai Second Medical
University, Shanghai 200025, China. maoeq@yeah.net
Telephone:
+86-21-64370045 Ext 666014
Received:
2002-08-06 Accepted: 2002-10-18
Abstract
AIM: To evaluate the impact of time
interval for hemofiltration (HF) on the prognosis of severe acute pancreatitis
(SAP).
METHODS: Thirty-six consecutive patients
with severe acute pancreatitis were included in the study. Atlanta
classification system was applied for stratification. They were randomly divided
into short veno-venous HF group, (SVVH, Group 1, 20 patients); and long veno-venous
HF group (LVVH, Group 2, 16 patients). In group 1, SVVH was stopped when the
abdominal signs disappeared, and heart rate and breath rate were less than 90
beats/min and 20 times/min, respectively. HF was stopped if SVVH was continued,
and when heart rate and breath rate were more than 90 beats/min and 20 times/min
again (Group 2). Except that the time interval for HF was different, other
parameters for HF were the same. And conservative curing rate, survival rate,
cost for hospital stay and length of hospital stay were observed.
RESULTS: Time interval for HF in Group 1
(3.81±1.3 hr) was shorter than that of in
Group 2 (9.38±2.9hr), P<0.01. Conservative
curing rate (90 %) in Group 1 was much higher than that in Group 2 (56.3 %) (P<0.05);
but cost in Group 1(RMB 56 600±56 400 Yuan) was lower than that in
Group 2 (RMB 137 000±105 000 Yuan) (P<0.05). And
the survival rate (95 %) in Group 1 was higher than that in Group 2 (81.3 %) (P<0.25);
however, hospital stay in Group 1 (44.3±41 days) was shorter than that in Group
2 (55.2±39.5 days) (P<0.2). So, the
prognosis was not improved through the prolongation of time interval for HF, but
side-effects were seen.
CONCLUSION: The prognosis was not further
improved by LVVH in the treatment of SAP, with side-effects. Time interval for
HF plays an important role in treatment of SAP in early stage. SVVH is thought
to be superior to LVVH; and LVVH is superior to CVVH in early (72hrs) treatment
of SAP.
Mao EQ, Tang YQ, Zhang SD. Effects of time interval for hemofiltration on the
prognosis of severe acute pancreatitis. World J Gastroenterol 2003; 9(2):
373-376
http://www.wjgnet.com/1007-9327/9/373.htm
INTRODUCTION
Up to date, strategies of treatments of severe
acute pancreatitis have been extensively developed, such as prolongation of
operation[1]; peritoneal lavage, blood purification[2],
and continuous arterial infusion of protease inhibitor[3], endothelin
receptor antagonist to reduce capillary leakage[4], and so on, in
addition to intensive care. But the mortality of SAP is still about 15-25 %[5].
So, how to further raise the survival rate is most difficult. A large amount of
cytokines[6] released from activated macrophages and other sites[7]
as well as cytokines cascades play an important role in deteriorating the
disease[8-11].
Clinical and experimental data suggest that
hemofiltration might be of benefit for amelioration of severe systemic
inflammatory response syndrome (SIRS) or multiple organ dysfunction[12-16]
and prevention of pancreatic necrosis[17,18]. Our data[17]
showed that pancreatic necrosis was prevented, and the prognosis was ameliorated
through short veno-venous hemofiltration (SVVH). However, it is reported that
better efficacy was also obtained from continuous veno-venous hemofiltration (CVVH)[2,19].
The aim of the present study is therefore to investigate the time-effect of
hemofiltration, by prolonging the time interval for HF in order to observe its
impact on clinical efficacy.
MATERIALS AND METHODS
Patients and groups
Patients
Thirty-six consecutive patients with SAP admitted to Ruijin Hospital, Shanghai,
China from April 1997 to May 2002, were included in the study. Prior to study,
all patients themselves or their relatives had been informed in detail, and
agreement was obtained. Atlanta classification system was applied for
stratification of patients with SAP[20]. Criteria for the study were
APACHEII score more than 8, with dysfunction of one or more organs, within 72
hours after onset of the disease and no indication for operation temporarily.
There were 25 men and 11 women, aged from 18 - 82 years. Etiologies included
hyperlipidemia (26 cases) with significantly increased triglyceride and billiary
disease (10 cases).
Groups The
patients were divided randomly into short veno-venous hemofiltration group
(Group 1, SVVH) and long veno-venous hemofiltration group (Group 2, LVVH). In
Group 1, consisted of 20 patients, 16 men and 4 women; aged 52.4±14.2 years, including 14 with
hyperlipidemia, 1 with hyperlipidemia and alcoholic abuse, and 5 with biliary
disease; In Group 2 was made up of 16 patients, 12 men and 4 women, aged 45.1±9.2 years, including 11 patients with
hyperlipidemia and 5 with biliary disease; and the time interval for HF ranged
from 5-20 hours.
APACHEII scores were 13.9±3.8 and 12.1±4.2 in the two groups; and there was no
difference (P>0.05) before hemofiltration.
Methods
Hemofilters HF
was performed using Diapact CRRT machine from B.Braun Co, Germany. And filters
used for HF were polysulphone filters (Fresenius Medical Care, AV 600 S, with
the cutoff of molecular weight of 30 KD); and extracorporeal lines were primed
with one liter of haparinized saline (5 000 IU/L). Vascular access was obtained
by two Gambro catheters inserted into each femoral vein. Low molecular weight
haparin (Fragmin, 5 000/ampule) was administered at dose of 100-140 IU/kg, and
bolus injection was made before HF. Ultrafiltrate was replaced with substitute
made according to electrolyte and blood glucose. Pre-dilution mode was used.
Extracoporeal blood flow ranged from 250 to 360 ml/min. Ultrafiltrating rate was
controlled within 50-300 ml/h.
Indication for stopping HF
In group 1, SVVH was stopped when the
abdominal signs disappeared, and heart rate and breath rate were less than 90
beats/min and 20 times/min, respectively. HF was stopped if SVVH was continued
when heart rate as well as breath rate were more than 90 beats/min and 20
times/min again (Group 2).
Follow-up
CT scanning was done every month; and
intra-pancreatic as well as extra-pancreatic changes were analyzed.
Prognostic indices
Conservative curing rate, hospital stay, cost
and survival rate were analyzed. The conservative cure referred to
intra-pancreatic and extra-pancreatic lesions absorbed entirely and /or formed
into pseudocyst without symptoms.
Statistical calculations
Data were reported as mean ± standard deviation, and analyzed using
Student's t and or qi square.
RESULTS
Time interval
Time interval for HF was 3.81±1.3 hrs in Group 1 and 9.38±2.9 hrs in Group 2, P<0.05.
Comparison of parameters of SVVH and LVVH
There was no difference in age, beginning
time for HF, APACHEII scores before HF, substitute rate, blood flow and
ultrafiltrate rate between the two groups, (Table 1).
There was significant difference in the amount of
purified blood, ultrafiltrate, heparin, colloid, substitute and filters between
the two groups, P<0.05; and these indices were closely related to the
time interval, (Table 1).
Table 1 Parameters of hemofiltration in two
groups
| Indices | Group 1 (≤5 h) | Group 2 (5-20 h) | P values |
| Number | 20 | 16 | |
| Age (years) | 52.4±14.2 | 45.1±9.2 | >0.05 |
| APACHE before HF | 13.9±3.8 | 12.1±4.2 | >0.05 |
| Beginning time (hr) | 45.9±21.2 | 37.4±12.5 | >0.05 |
| Rate of substitute (ml/h) | 2700±500 | 2880±300 | >0.05 |
| Blood flow (ml/min) | 200~250 | 250~360 | >0.05 |
| Rate of ultrafiltrate(ml/h) | 342.5±251 | 240±72 | >0.05 |
| Time interval (hr) | 3.81±1.3 | 9.38±2.9 | <0.01 |
| Colloid volume (ml) | 700±258.2 | 1500±852.9 | <0.01 |
| The amount of haparin (IU) | 7700±2341.1 | 12000±6000 | <0.01 |
| Substitute volume(L) | 9.5±3.2 | 35.1±16.5 | <0.01 |
| Ultrafiltrate Volume(ml) | 1040±520 | 2400±700 | <0.01 |
| Filters | 1.44±0.73 | 2.75±1.4 | <0.05 |
Prognosis
Conservative curing rate was more
significantly increased in Group 1 than in Group 2, P<0.05; but cost
was significantly decreased, P<0.05, ( Table 2).
Survival rate was significantly higher in Group 1
than in Group 2, P<0.25; but hospital stay was significantly
shortened, P<0.2.
Table 2 Indices of prognosis of severe acute
pancreatitis
| Indices | Group1 (≤5 h) | Group 2 (5-20 h) | P values |
| Number | 20 | 16 | |
| Conservative curing rate (%) | 90 %(18/20) | 56.3 %(9/16) | <0.05 |
| Survival rate (%) | 95 %(19/20) | 81.3 %(13/16) | <0.25 |
| Cost (×104 yuan) | 5.66±5.64 | 13.7±10.5 | <0.05 |
| Hospital stay (d) | 44.3±17.3 | 55.2±29.5 | <0.2 |
DISCUSSION
Up to date, strategies have been used to target
cytokines, such as cytokine anti-body, purification and transient transfection
of human IL-10 gene. In term of neutralization of antibody, for example, Hughes[8,9]
reported that scores for pathology of pancreas were significantly improved by
TNFa blockade. But, the method is only one antibody to one antigen to neutralize
cytokine, and it is far from combating with complicated cytokines network.
According to Grewal[21] and Kingsnorth[10], despite
amelioration of ascites production by TNFa blockade, histologic evaluation
scoring was not statistically different. And IL-1r antagonist only modified the
changes in vital organs induced by SAP[22], it did not affect the
degree of local pancreatic insult. This method is controversial and has not been
reported in clinical trial till now. Denham[23] demonstrated that
transient transfection of a human IL-10 gene decreased the severity of
pancreatitis during acute inflammatory process. It is only an animal experiment,
that blood purification[14,18,24], such as plasmapheresis,
hemadsorption, hemofiltration, can remove the mediators from circulation. Among
them, hemofiltration is used widely in clinics.
In 1991, Blinzler reported that CVVH can be used
to treat SAP at early stage[18], although no organ
failure happened. This is the earliest report of CVVH to blockade pancreatic
necrosis. In 1994, Gehbart[2] reported that CVVH was applied to 11
patients with most serious clinical course and multi-system failure. The overall
lethality rate of the treated patients was 7.9 %. In 1998, Schmidt[25]
suggested that CVVH had been proven to be of no efficacy. In 1999, Yekebas[19]
performed animal experiment to investigate the effects of CVVH on SAP, showing
that the survival time was significantly prolonged. In 2001, Pupelis[26]
applied that hemodialysis, hemofiltration, plasmapheresis, hemadsorption to SAP
patients concomitant with organ failure, and achieved a good result.
These investigations have shown that CVVH is of
benefit for treatment of SAP or multiple organ dysfunction secondary to SAP. We
performed SVVH within 72 hours after onset of the disease, and obtained
satisfactory clinical efficacy[17]. The present study showed that
survival rate in Group 1 was 95 %, which was much higher than that of 92 % from
the 11 patients in Gehbart's report[2].
Pupelis[26] reported a survival rate of 80 % using CVVH and
hemodialysis to treat SAP, which is the same as that of non-hemofiltration[5];
and its conservative curing rate (38.2 %,13/34) is much lower than ours (90
%,18/20), (c2=13.8,
P=0.0 002). Miller[27] reported a survival rate of only 71.4 %
(5/7) using CVVH to treat SAP. It is much lower than ours (95 %, 19/20), (c2=2.917,
P=0.088). In the present study, the conservative curing rate, cost,
hospital stay and survival rate were improved in SVVH group as compared with
LVVH group. The conservative curing rate and cost were especially improved
significantly (P<0.05). Why is the efficacy decreased in LVVH group or
CVVH group?
In the early stage of SAP, pro-inflammatory and
anti-inflammatory cytokines are inter-related in a united entity under
pathological state. Any of them which is over-produced or less-produced, will
contribute to different pathophysiologic response, such as systemic inflammatory
response syndrome (SIRS), compensatory anti-inflammatory response syndrome
(CARS), Mixed antagonist response syndrome (MARS)[28,29]. According
to this assumption, pro-inflammatory and anti-inflammatory cytokines should be
in a dynamic balance state through cytokines eliminated partly. The
pro-inflammatory and anti-inflammatory level was modulated through
4h-SVVH[17]; the former (TNF, IL-1, IL-8, IL-6 and sIL-2R) was
decreased and the latter (IL-2, IL-10) was increased. Monocyte cytokine (TNF,
IL-6, IL-8) production was increased in association with systemic complications
in acute pancreatitis[30]; and IL-10 prevented pancreatic necrosis[31,32]
as well as death in lethal necrotizing pancreatitis[33]. SIRS was
doomed to be interrupted and the severity of SAP was decreased significantly.
This demonstrates that dynamic balance of pro- and anti-inflammatory cytokines
is established at the pathological state.
When T and B lymphocytes and monocytes are
activated, membrane receptor of IL-2 would be expressed; and soluble receptor of
IL-2 (sIL-2R) is liberated into circulation[34] Simultaneously.
sIL-2R can combine with IL-2; and if it is over produced, serum level of IL-2
will be decreased. It is reported that IL-2 production was decreased in acute
pancreatitis[35]. And IL-2 is the major factor that activated T and B
lymphocytes and decreased infection rate[36]. Therefore,
over-produced sIL-2R may lead to decreased immune function. In clinical trial[17],
serum level of sIL-2R was decreased significantly through SVVH, however, serum
concentration of IL-2 was increased, and the infection rate was decreased. At
the same time, the time of infection occurrence was postponed, suggesting that
immune function has been up-regulated. CVVH may contribute to immune-paralysis
due to over-removed cytokines and inhibit the up-regulation of PMN phagocytosis
capacity after intra-abdominal sepsis[37]. Thus, dynamic balance
obtained between pro-inflammatory cytokines and anti-inflammatory cytokines is
imbalanced again. So, there is no difficulty in understanding increased
infection and earlier operation in LVVH group.
During conservative treatment, two factors,
immune function of body and optimal application of antibiotics, are important in
the prevention of pancreatic infection. Ciprofloxacin and Metronidazole were
infused to 36 patients on admission. If the body temperature was increased,
carpenems plus fluconazole would be infused empirically. Simultaneously, body
fluids were cultured. If the temperature was controlled, antibiotics were not
stopped until the enteral nutrition had been fed for one week. On the contrary,
antibiotics were changed according to the cultures. Given temperature was still
abnormal through optimal antibiotics and strengthened immune function, and
infection in other sites was excluded, drainage of infected necrotic pancreata
should be performed. This demonstrated that pancreatic infection had not been
controlled by intensive treatments from 48 to 72 hours.
In Group 1, pseudocysts were entirely absorbed
from 2 months to 2 years in 15 patients, and 3 patients underwent
jejuno-pseudocyst Roux-en-Y anastomosis or gastropseudocyst anastomosis. Seven
patients underwent drainage within 20 to 30 days after onset of the disease in
Group 2.
According to our clinical trial, once indices for
cessation of hemofiltration were reached, it should be stopped immediately.
Additionally, although indices for stopping HF has not been reached with more
than 8 h-HF, hemofiltration should also be stopped as we seek other factors
leading to the change of heart rate and breath rate, because they may be
affected by other factors.
On admission, patients should be strictly
estimated that whether he or she has the indication for SVVH. If he or she is
below 70 years old, time is within 72 hours after onset of the disease and
without billiary obstruction, it is wise to perform SVVH. It did not reach the
peak of the disease until the time interval for abdominal pain was 72 hours.
Within 72 hours, cascades of cytokines were blockaded easily, and vicious cycle
was not formed between secondary chemokines released[38] and
cytokines. Thus, 72 hours should be emphasized heavily. And the earlier the
hemofiltration began, the better the result was. Patients with ACST underwent
operation, EST or nasobilliary catheter inserted to drain bile. SVVH could still
be performed after these.
Although prognosis was improved through SVVH, it
is only a new method in synthetical treatment strategies for SAP. It can not
replace other measures. For example, Pixiao (a traditional Chinese medicine) is
applied continuously to the whole abdomen after hemofiltration is stopped, and
until it has no effects.
In summary, SVVH is superior to LVVH, and LVVH is
better than CVVH in the treatment of SAP in early stage. Much more significant
side-effects occurred due to longer time interval for HF.
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Edited by Ma JY