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Table 1 Summary of studies evaluating the effect of glucocorticosteroids for acute pancreatitis on clinical score, duration of hospitalization, C-reactive protein, and histopathologic score

From: Corticosteroid treatment for acute/acute-on-chronic experimental and naturally occurring pancreatitis in several species: a scoping review to inform possible use in dogs

Study

Level of evidence, study design and methodological quality (for details see Table 2)

Species

Number of subjects in groups

Acute pancreatitis type

Treatment: Type of GC, dose, duration, administration route and timing

Other treatment (GC group + model controls)

Data collection and timing, post induction unless otherwise stated

Outcome: Clinical score

Outcome: CRP

Outcome: Duration of hospitalisation

Outcome: Mortality

Outcome: Pancreas histopathology

Okanishi et al. [57]

LOE III

Non-RCT

Moderate estimated risk of bias, Moderate number of well characterised dogs in each group

Dogs

Model controls: 20

GC group: 45

Spontaneous AP

Prednisolone 1 mg/kg/day SC, from diagnosis to discharge

IV fluids, maropitant, famotidine, enrofloxacin, fentanyl, multivitamin solution

Daily clinical score evaluation in hospital, CRP, mortality. Follow up 1 month after diagnosis

Days until clinical score ≤ 2/3 was significantly lower in GC group (P < 0.001) (median 4 vs 7 days)

Days until CRP had reached < 2 mg/dL was significantly lower in GC group (P < 0.001) (median 4 vs 8 days)

Significantly shorter in GC group (P = 0.002) (median: 5 vs 8 days)

1-month survival was significantly higher in GC group (P = 0.005) (88.7% vs 57.9%)

NA

Studley and Schenk 1982 [39] Experiment 1

LOE II

RCT, low estimated risk of bias, very small number of poorly characterised dogs in each group

Dogs

Model controls: 8

Group 1: 6

Group 2: 6

Induced AP: 10 mL bile injected into the pancreatic duct

Hydrocortisone 2.86 mg/kg IV, then 1.43 mg/kg q8h

Controls: No GC

Group 1: GC 6 h post induction

Group 2: GC 12 h post induction

IV fluids: 5% dextrose in 0.2% saline 10 mL/kg SC q8h

Survival up to 72 h

NA

NA

NA

Survival time increased in treatment groups controls: 18.8 h

Group 1: 40.2 h (P < 0.05)

Group 2: 48.3 h (P < 0.03)

No difference between treatment groups

NA

Studley and Schenk [39]

Experiment 2

LOE II

RCT, low estimated risk of bias, very small number of poorly characterised dogs in each group

Dogs

Model controls: 6

Group 1: 5

Group 2: 6

Induced AP: 10 mL bile injected into the pancreatic duct

Hydrocortisone

Controls: No GC

Group 1:2.86 mg/kg IV, 6 h post induction, then 1.43 mg/kg q8h

Group 2: Hydrocortisone 14.3 mg/kg 6 h post induction, then q8h

Fluid replacement: 5% dextrose in 0.2% saline 10 mL/kg SC q8h

Survival up to 72 h

NA

NA

NA

Survival time increased in treatment groups

Controls: 27 h Group 1: 45.6 h (P < 0.05)

Group 2: 41.6 h (P < 0.05)

No difference between treatment groups

NA

Attix et al. [58]

LOE III

Controlled trial, high estimated risk of bias, very small number of poorly characterised dogs in each group

Dogs

Model controls: 4

GC group: 4

Induced AP: Oleic acid 5 mL/kg injected into the main pancreatic duct

Dexamethasone 0.06 mg/kg IV q24h for 8 days, start 24 h post induction

IV fluids incl. glucose for 5 days postop. Procaine penicillin G 20.000 U/kg IM q12h, Kanamycin sulfate 5 mg/kg IM q8h, NPO for 8 days

Clinical evaluation 3 times daily, histopathology at day 8, technique and results not shown, only photos

No clinical difference

NA

NA

NA

No results/conclusions for difference in histopathology among groups reported

Stewart et al. [59]

LOE III

Controlled trial, high estimated risk of bias, small number of poorly characterised dogs in each group

Dogs

Model controls: 16

GC group: 25

Induced AP: A solution of trypsin and 4% sodium taurocholate injected into the main pancreatic duct

Cortisone acetate 100 mg IM, as soon as the abdomen could be closed, then 50 mg q12h for 4 days, then gradually withdrawn

None stated

Survival, pancreas histopathology when survival was assured (day 5–60), technique and results not shown

NA

NA

NA

Survival: control 6%,

GC group 48%

GC group had decreased oedema and inflammation in the first few days, less apparent in animals autopsied after ≤ 5 days

Imahori et al. [60]

Study 1

LOE III

Controlled trial, low estimated risk of bias, small number of poorly characterised dogs in each group

Dogs

Model controls: 14

GC group: 14

Induced AP: Autologous bile injected into the pancreatic duct

Hydrocortisone 2.86 mg/kg IV, 6 h post induction, then 1.34 mg/kg q8h

Fluid treatment 5% dextrose in 0.2% saline 10 mL/kg SC q8h

72 h survival, histopathology at death or 72 h, score 0–3 (oedema, PMN leucocyte infiltration, vascular thrombosis, necrosis, haemorrhage)

NA

NA

NA

Significantly increased duration of survival in GC group (P < 0.01)

Acinar necrosis significantly decreased in GC group (P < 0.05)

Imahori et al. [60]

Study 2

LOE III

Controlled trial, high estimated risk of bias, very small number of poorly characterized dogs

Dogs

Model controls: 6

GC group: 5

Induced AP: Autologous bile injected into the pancreatic duct

Hydrocortisone 14.3 mg/kg at 6, 14 and 22 h post induction

Fluid treatment 5% dextrose in 0.2% saline 10 mL/kg SC q8h

Ultrastructural changes to the pancreas at 24 h

NA

NA

NA

NA

Pancreatic structural integrin better preserved in the GC group

Kaplan et al. [65]

LOE III

Retrospective case control study, high estimated risk of bias, small number of fairly well characterised patients in each group

Humans

Model controls: 48

GC group: 15 GC

Spontaneous Acute oedematous: 51

Acute haemorrhagic/necrotising: 12

Hydrocortisone 100-200 mg IV every 6-8 h for 2–3 days, then tapered

Nasogastric suction, anticholinergics, antibiotics, IV fluids

Clinical evaluation, mortality

Dramatic response reported

NA

NA

Oedematous AP: all survived

Haemorrhagic AP: Overall mortality 8/12 (67%)

GC group 5/9 (55%)

NA

Liu et al. [40]

LOE II

Randomised controlled trial, moderate estimated risk of bias, moderate number of poorly characterised patients in each group

Humans

Model controls: 53

GC group: 26

Spontaneous AP

Dexamethasone 20–30 mg then 30-60 mg/day, tapered over 3–5 days, Dextran 500 mL/day and Salvia miltiorrhiza 20–30 mL, treatment initiated at diagnosis

NPO, pancreatin secretion inhibition, antibiotics, fluids, parenteral nutrition

Mortality

NA

NA

NA

Reduced in GC group 11.54% vs 32.08% (P < 0.05)

NA

Eklund et al. [37]

LOE III

Retrospective case control-study, low estimated risk of bias, small number of well characterised patients in each group

Humans

Model controls: 11

GC group: 10

Spontaneous AP

Hydrocortisone 3–400 mg/day, started 4-11d after symptom onset

Ventilation, IV fluids antibiotics (cefuroxime mostly)

CRP up to 48 h, 30-day mortality

NA

CRP significantly lower in GC group at 48 h (P = 0.043), not at 24 h

NA

30-day mortality

GC group 30%, controls 36%

NA

Wang et al. [66]

LOE IV

Case-series, high estimated risk of bias, moderate number of fairly well characterised patients in the group

Humans

Model controls: 0 (literature reference)

GC group: 32

Spontaneous AP

Dexamethasone 0.5–1 mg/kg q24h for3-5 days, starting 8 h to 4 days after onset of symptoms

Dextran-40 500–1000 mL/day for 7 days

Nasogastric tube decompression, oxygen, IV fluids, antibiotics (imipenem)

Clinical evaluation, mortality

4-8 h after treatment start pain was relieved

NA

NA

GC group: 12.5% literature: 40%

NA

Wan et al. [38]

LOE II

RCT, low estimated risk of bias, moderate number of well characterised patients in each group

Humans

Model controls: 35

GC group: 35

Spontaneous AP

Dexamethasone IV 1 mg/kg q6h for 3 days

NPO, IV fluids, analgesia, proton pump inhibitors, parenteral nutrition, modified Dachengqi Decoction, plasma and albumin if necessary, 14d antimicrobials

Observation and follow up for 1 month

NA

NA

Duration of hospitalisation significantly reduced in GC group (P = 0.03)

32.5 vs 40.2 days

GC group: 8.6%, model controls: 14.3% (NS)

NA

Zhang et al. [41]*

LOE II

RCT, moderate estimated risk of bias, moderate number of well characterised rats in each group

Rats

Model controls: 45

GC group: 45

Induced, sodium taurocholate 3.5% 1 mL/kg injected into bile-pancreatic duct

Dexamethasone 5 mg/kg IV single dose, 15 min post induction

None stated

Survival at 3,6,12 h, pancreas histopathology score 0–4 (oedema, acinar necrosis, inflammation, perivascular infiltrate, haemorrhage, fat necrosis)

NA

NA

NA

No difference in mortality

Pancreas histopathology score lower in GC group vs model controls at 3 and 6 h (P < 0.05), and at 12 h (P < 0.01)

Schulz et al. [42]

LOE II

RCT, low estimated risk of bias, small number of well characterised rats in each group

Rats

Model controls: 15

GC group: 15

Induced AP, sodium taurocholate 3.5% 2 mL/kg injected into the biliary-pancreatic duct

Methylprednisolone 25 mg/kg IV, 1 h post induction, followed by CRI 0.125 mg/kg

Ringers lactate 0.5 mL/h

Survival, histopathology at 20 h score 0–3 (oedema, inflammatory infiltration, haemorrhage, necrosis, fat necrosis)

NA

NA

NA

No difference in survival

No difference in histopathology

Gloor et al. [61]

Experiment 1

LOE III

Controlled trial, low estimated risk of bias, moderate number of well characterised rats in each group

Rats

Model controls: 32

GC group: 32

Induced AP, cerulein 5 µg/kg/h over 6 h IV (oedematous pancreatitis)

Hydrocortisone 10 mg/kg IV 10 min post induction

Fluid replacement

Histopathology at 1.5 h, 3 h, 6 h, 12 h; score 0–4 (oedema, inflammatory infiltration), 0–7 (necrosis, haemorrhage)

NA

NA

NA

NA

No difference in histopathology score, results not shown

Gloor et al. [61]

Experiment 2

LOE III

Controlled trial, low estimated risk of bias, moderate number of well characterised rats in each group

Rats

Model controls: 40

GC group: 40

Induced AP, sodium taurocholate 5% injected into the biliopancreatic duct (necrotising pancreatitis)

Hydrocortisone 10 mg/kg IV 10 min post induction

Fluid replacement

Histopathology at 1.5 h, 3 h, 6 h, 12 h; score 0–4 (oedema, inflammatory infiltration), 0–7 (necrosis, haemorrhage)

NA

NA

NA

NA

No difference in histopathology score, results not shown

Gloor et al. [61]

Experiment 3

LOE III

Controlled trial, low estimated risk of bias, very small number of well characterised rats in each group

Rats

Model controls: 8

GC group: 21

Induced, sodium taurocholate 5% injected into the biliopancreatic duct (necrotising pancreatitis)

Hydrocortisone 10 mg/kg IV 10 min post induction

Fluid replacement

72 h survival

NA

NA

NA

Reduced in GC group versus model controls (P = 0.01)

NA

Cosen-Binker et al. [43]

LOE II

RCT, moderate estimated risk of bias, small number of well characterised rats in each group

Rats

Model controls: 16

Group 1: 16

Group 2: 16

Induced AP, sodium taurocholate 7% injected into the biliopancreatic duct

Hydrocortisone SC 4 h post induction

Model controls: No GC

Group 1: GC 4 mg/kg

Group 2: GC 2 mg/kg

None stated

Histopathology at 8 h post induction, score 0–4 (oedema, haemorrhage, leucocyte infiltration, acinar necrosis, fat necrosis)

NA

NA

NA

NA

Unclear description of results numerical and statistical differences were found

Cosen-Binker et al. [44]

LOE II

RCT, low estimated risk of bias, small number of well characterised rats in each group

Rats

Model controls: 16

Group 1: 16

Group 2: 16

Group 3: 16

Group 4: 15

Induced AP, sodium taurocholate 8% 1 mL injected into the biliopancreatic duct

Hydrocortisone 6 mg/kg SC or Prednisolone 0.5 mg/kg SC 1 h or 4 h post induction

Controls: No GC

Group 1: HC 1 h

Group 2: HC 4 h

Group 3: Pred 1 h

Group 4: Pred 4 h

None stated

CRP, histopathology at 10 h, score 0–4 (oedema, haemorrhage, leukocyte infiltration, acinar necrosis, fat necrosis)

NA

HC or pred 1 h post induction improvement of CRP (P < 0.05)

HC or pred 4 h post induction no difference

NA

NA

HC or pred 1 h post induction improvement of histopathology score (P < 0.05). HC or pred 4 h post induction no difference

Jha et al. [45]

LOE II

RCT, high estimated risk of bias, moderate number of well characterised rats in each group

Rats

Model controls: 24

GC group: 24

Induced AP, sodium taurocholate 4% 1 mL/kg injected into the biliopancreatic duct

Dexamethasone 0.5 mg/kg IV after induction

None stated

Histopathology at 3 h, 6 h and 12 h, score 0–4 (oedema, acinar necrosis, haemorrhage, fat necrosis, inflammation, perivascular infiltration), TEM of pancreatic tissue

NA

NA

NA

NA

Authors claim marked difference in histopathology and TEM pathologic changes between groups at 12 h

Results not shown

Melo et al. [46]

LOE III

RCT, low estimated risk of bias, very small number of well characterised rats in each group

Rats

Model controls: 8

GC group: 8

Induced AP, l-arginine 2.5 g/kg IP twice with 1 h interval

Methylprednisolone 30 mg/kg PO 1 h after induction

None stated

Histopathology at 24 h, score 0–3 (oedema, leukocyte infiltration, haemorrhage, acinar vacuolization & necrosis)

NA

NA

NA

NA

Reduced histopathology score on all parameters in GC group compared to model controls (P < 0.05)

Ramudo et al. [62]

LOE III

Controlled trial, moderate estimated risk of bias, very small number of well characterised rats in each group

Rats

Model controls: 6

GC group: 6

Induced AP, bile-pancreatic duct obstruction (BPDO)

Dexamethasone 1 mg/kg IM 1 h post induction

Buprenorphine 0.2 mg/kg IM

Histopathology at 3 h and 12 h, score 0–3 (oedema, inflammatory cells, vacuolisation, necrosis)

NA

NA

NA

NA

Reduced oedema and leucocyte infiltration at 12 h in GC group compared to model controls (P < 0.05)

Ramudo et al. [47]

LOE II

RCT, low estimated risk of bias, unknown number of well characterised rats in each group

Rats

Model controls: not stated

GC group: not stated

Induced AP, sodium taurocholate 3.5% 0,1 mL injected into the biliopancreatic duct

Dexamethasone 1 mg/kg IM 1 h post induction

Buprenorphine 0.2 mg/kg IM

Histopathology at 3 h and 6 h, score 0–3 (oedema, inflammatory cells, vacuolisation, necrosis)

NA

NA

NA

NA

Reduced necrosis at 6 h in GC group compared to model controls (P < 0.05)

Ou et al. [48]**

LOE II

RCT, high estimated risk of bias, moderate number of well characterised rats in each group

Rats

Model controls: 36

GC group: 36

Induced, sodium taurocholate 3.5% 0.1 mL/100 g injected into the biliopancreatic duct

Dexamethasone 0.5 mg/100 g IV 15 min post induction, then CRI 0.05 mg/100 g/h (dose only mentioned in Zhang et al. 2010)

None stated

Mortality rate, Pathological severity score at 3 h, 6 h, 12 h (not further explained), but results shown

NA

NA

NA

Lower in GC group compared to model controls at 12 h (P < 0.05)

Reduced histopathology severity score at 12 h in GC group compared to model controls (P < 0.05)

Zhao et al. [49]

LOE II

RCT, high estimated risk of bias, small number of well characterised rats in each group

Rats

Model controls: 15

GC group: 15

Induced AP, sodium taurocholate 5% injected into the biliopancreatic duct

Dexamethasone 5 mg/kg IV following induction

None stated

Histopathology, scoring technique not stated, results not shown

NA

NA

NA

NA

Author claims Oedema and necrosis reduced in GC group compared to model controls especially at 12 h

Foitzik et al. [50]

LOE II

RCT, moderate estimated risk of bias, small number of well characterised rats in each group

Rats

Model controls: 10

Group 1: 10

Group 2: 10

Group 3: 12

Induced AP: Glycodeoxycholic acid 10 mM injected into the biliopancreatic duct, then IV 5 µg/kg/h cerulein over 6 h

Prednisolone started 6 h after induction, q8h for 24 h

Ccontrols: No GC

Group 1: GC 2 mg/kg/day

Group 2: GC 10 mg/kg/day

Group 3: GC 50 mg/kg/day

IV fluids 6 mL/kg/h for 8 h after induction

Mortality, histopathology 6 h after last treatment, score 0–4 (oedema, acinar necrosis, haemorrhage, fat necrosis, inflammation, perivascular infiltrate)

NA

NA

NA

Mortality 20–40%, no difference among groups

Histopathology score for acinar necrosis: No difference among groups

Biradar and Veeresh [51]

LOE II

RCT, high estimated risk of bias, very small number of well characterised rats in each group

Rats

Model controls:6

GC group: 6

Induced: 2 Intraperitoneal injections of l-arginine 2.5 g/kg, 1 h apart

Methylprednisolone 30 mg/kg/day PO 1 h post induction

None stated

CRP histopathology 24 h after last L-arginine injection, score 0–3 (oedema, acinar cell degeneration, interstitial inflammation, haemorrhage),

NA

CRP results for GC group not show

NA

NA

Authors claim less oedema, Inflammation, acinar cell degeneration & necrosis in GC group, results not shown

Biradar and Veeresh [52]

LOE II

RCT, high estimated risk of bias, very small number of well characterised rats in each group

Rats

Model controls: 8

GC group: 8

Induced: 2 Intraperitoneal injections of l-arginine 2.5 g/kg, 1 h apart

Methylprednisolone 30 mg/kg/day PO 1 h post induction

None stated

CRP, histopathology 24 h after last L-arginine injection, score 0–3 (oedema, acinar cell degeneration, interstitial inflammation, haemorrhage)

NA

CRP results for GC group not shown

NA

NA

Authors claim less oedema, Inflammation, acinar cell degeneration & necrosis in GC group, results not shown

Duan et al. [63]

LOE III

Controlled trial, moderate estimated risk of bias, moderate number of well characterised rats in each group

Rats

Model controls: 24

GC group: 21

Induced AP: sodium taurocholate 5% 1 mL/kg injected into the intracholangiopancreatic duct

Methylprednisolone 30 mg/kg IV 30 min after induction

6 mL/kg/h SC saline

Mortality

NA

NA

NA

4/24 model controls died, 0/21 in GC group died

NA

Wang et al. [36]

LOE II

RCT, moderate estimated risk of bias, moderate number of well characterised rats in each group

Rats

Model controls: 25

GC group: 25

Induced AP: sodium taurocholate 5% 1 mL/kg injected into the intracholangiopancreatic duct

Dexamethasone 0.5 mg/kg IV 5 min after induction

None stated

Mortality, histopathology at 12 h, score 0–4 (oedema, acinar necrosis, haemorrhage, fat necrosis, inflammation, perivascular infiltrate)

NA

NA

NA

Model controls: 42.9%

GC group: 0% (P < 0.01)

Haemorrhage & acinar necrosis less in GC group compared to model controls (P < 0.05)

Results not shown

Liu et al. [53]

LOE II

RCT, low estimated risk of bias, small number of fairly well characterised rats in each group

Rats

Model controls: 16

GC group: 16

Induced AP: sodium taurocholate 5% 0.4 mL/kg injected into the intracholangiopancreatic duct

Glucocorticoid (type not stated) 20 mg/kg SC 1 h after induction

None stated

Mortality 24 h postinduction, histopathology at 3 h, 6 h and 12 h, score 0–3 (oedema, acinar necrosis, inflammatory infiltrate, haemorrhage, fat necrosis, perivascular inflammation)

NA

NA

NA

Model controls 50%

GC group 40%, Not significant

Histopathology scores were lower in the GC group compared to model controls (P < 0.05)

Sha et al. [54]

LOE II

RCT, low estimated risk of bias, moderate number of well characterised rats in each group

Rats

Model controls: 24

GC group: 24

Induced AP: Taurocholate 40 g/L 1 mL/kg injected into the Intracholangiopancreatic duct

Dexamethasone 0.5 mg/kg IV after induction

None stated

Histopathology score 0–3 (oedema, acinar necrosis, haemorrhage, fat necrosis, inflammation, perivascular infiltrate and TEM at 3 h, 6 h and 12 h

NA

NA

NA

NA

Histopathologic scores lower in GC group compared to model controls (P < 0.05)

Ultrastructural changes were markedly less in the GC group

Kilic et al. [55]

LOE II

RCT, low estimated risk of bias, very small number of well characterised rats in each group

Rats

Model controls: 8

GC group: 8

Induced AP:

cerulein injected IP hourly 5 times, given a total of 80 mg/kg

Methylprednisolone 10 mg/kg IM twice hourly at 1 h after last cerulein injection

None stated

Histopathology at 20 h, score 0–3 (oedema), score 0–4 (inflammation, necrosis, vacuolisation)

NA

NA

NA

NA

Histopathology scores lower in GC group compared to model controls (P < 0.01)

Cui et al. [56]

LOE II

RCT, high estimated risk of bias, very small number of well characterised rats in each group

Rats

Model controls: 6

GC group: 6

Induced AP:

sodium taurocholate 5% 1 mL/kg injected into intracholangiopancreatic duct

Dexamethasone 1 mg/kg IP 3 h post induction

None stated

Histopathology at 24 h post treatment, no technique or results shown, only photos

NA

NA

NA

NA

Histopathological changes were alleviated in GC group according to authors

Zhao et al. [64]

Group 1

LOE III

Controlled trial, high estimated risk of bias, small number of well characterised mice in each group

Mice

C57BL/6

Model controls: 34

Group 1: 20

Group 2: 15

Induced: l-arginine 2.5 mg/g injected IP twice with 1 h interval

Dexamethasone 30 min post induction

controls: No GC

Group 1: GC 0.4 mg/kg IV

Group 2: GC 4 mg/kg IV

Geldanamycin 1 or 10 g/kg IV 10 min post induction

Mortality at 24 h, histopathology at 24 h, no technique or results shown, only photos

NA

NA

NA

Model controls: 23.5%

Group 1: 15%

Group 2: 6.7%

Pictures of histopathology are shown but not discussed

Zhao et al. [64]

Group 2

LOE III

Controlled trial, moderate estimated risk of bias, small number of well characterised mice in each group

Mice

BALB/c

Model controls: 34

Group 1: 20

Group 2: 15

Induced: l-arginine 2.5 mg/g injected IP twice with 1 h interval

Dexamethasone 0.4 or 4 mg/kg IV 30 min post induction

controls: No GC

Group 1: GC 0.4 mg/kg IV

Group 2: GC 4 mg/kg IV

Geldanamycin 1 or 10 g/kg IV 10 min post induction

Mortality at 24 h, histopathology at 24 h, no technique or results shown, only photos

NA

NA

NA

Model controls: 52.9%

Group 1: 45%

Group 2: 6.7%

Pictures of histopathology are shown but not discussed

  1. Model controls: AP cases receiving no or standard (other) treatment, GC group: AP cases treated with GC in addition to treatment for model controls
  2. *10 articles were found describing the same experimental study, the most relevant was used as reference here, the other 9 was full text excluded, see Fig. 1, a reference list is available at request
  3. **2 articles were found describing the same experimental study, the most relevant was used as reference here, the other was full text excluded, see Fig. 1, a reference list is available at request
  4. AP: acute pancreatitis; CRI: constant rate infusion; CRP: C-reactive protein; GC: glucocorticoid; h: hours; HC: hydrocortisone; IM: intramuscular; IV: intravenous; IP: intraperitoneal; NA: not applicable; NPO: nothing per os; Pred: Prednisolone; RCT: randomised controlled trial; SC: subcutaneous; TEM: transmission electron microscopy