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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