Methods of review and trials details

Details of 44 included trials ...
 

Review methods and search strategy

We aimed to identify all unconfounded randomised controlled trials of the timing (early versus late) or volume (none versus any, more versus less) of fluid administration in animal models of uncontrolled haemorrhage. The resuscitation fluid could include crystalloid solutions (isotonic or hypertonic), colloids, plasma or blood. Trials in which the timing or volume of fluid administration was confounded by the type of intravenous fluid given, for example a trial comparing the administration of 100 ml of colloid with 50 ml blood, were excluded. The outcome measure was mortality at the end of the follow up period scheduled for each trial.

We sought mortality data in simple categorical form and did not extract data on time to death. If a trial did not report the number of deaths in each group, we sought these data from the authors. In this paper we report the comparison: any fluid resuscitation versus none. If several different fluid resuscitation groups were compared with no resuscitation, the fluid groups were combined to create a dichotomy. The search strategy shown below was used to search Medline and Embase. There was no language restriction.

Two reviewers examined the electronic search results for reports of possibly relevant randomised controlled trials and these were retrieved in full. Two reviewers applied the selection criteria independently to the trial reports, resolving disagreements by discussion with a third. We searched the reference lists of included trials and contacted the authors to ask about unpublished studies. Two reviewers independently extracted information on the method of randomisation and allocation concealment, the number of animals in each group, the type of animal model, the nature of the intervention and the numbers of deaths in each group. Reviewers were not blinded to the authors or journal when extracting data. Where there was insufficient information in the published report we contacted the authors for clarification.

Search strategy used on Medline and Embase

#1 (hemorrhag* or haemorrhag* or bleeding or hypovolaem* or hypovolem*) in ti) or (hemorrhag* in mesh)

#2 volume* or fluid* or crystal* or colloid* or plasma or saline or hypertonic

#3 controll* or random* or (randomi* in pt) or (comparative* in tg) or comparative or experiment* or group or groups or trial* or assigned

#4 #1 and #2 and #3

#5 TG = "ANIMAL"

#6 #4 and (TG = "ANIMAL")

Included trials

  1. Alspaugh DM, Sartorelli K, Shackford SR, Okum EJ, Buckingham S, Osler T. Pre-hospital resuscitation with phenylephrine in uncontrolled hemorrhagic shock and brain injury. J Trauma 2000;48:851-64.
  2. Bickell WH, Bruttig SP, Millnamow GA, O’Benar J, Wade CE. Use of hypertonic saline/dextran versus lactated Ringer’s solution as a resuscitation fluid after uncontrolled aortic hemorrhage in anesthetised swine. Ann Emerg Med 1992;21:1077-85.
  3. Bilynskyj MC, Errington ML, Velasco IT, Silva R. Effect of hypertonic sodium chloride (7.5%) on uncontrolled hemorrhage in rats and its interaction with different anesthetic procedures. Circulatory Shock 1992;36:68-73.
  4. Burris D, Rhee P, Kaufmann C, Pikoulis E, Austin B, Eror, et al. Controlled resuscitation for uncontrolled hemorrhagic shock. J Trauma 1999;46:216-23.
  5. Capone AC, Safar P, Stezoski W, Tisherman S, Peitzman AB. Improved outcome with fluid restriction in treatment of uncontrolled hemorrhagic shock. J Am Coll Surg 1995;180:49-56.
  6. Capone AC, Safar P, Stezoski SW, Peitzman A, Tisherman S. Uncontrolled hemorrhagic shock outcome model in rats. Resuscitation 1995;29:143-152.
  7. Craig RL, Poole GV. Resuscitation in uncontrolled hemorrhage. Am Surg 1994;60:59-62.
  8. Dronen SC, Stern SA, Wang X, Stanley M. A comparison of the response of near-fatal acute hemorrhage models with and without a vascular injury to rapid volume expansion. Am J Emerg Med 1993;11:331-5.
  9. Elgjo GI, Knardahl S. Low-dose hypertonic saline (NaCl 8.0%) treatment of uncontrolled abdominal hemorrhage: effects on arterial versus venous injury. Shock 1996;5:52-8.
  10. Greene SP, Soucy DM, Song WC, Barber AE, Hagedorn FN, Illner HP, et al. Early isotonic saline resuscitation from uncontrolled hemorrhage in rats. Surgery 1998;124:568-74.
  11. Feldman Z, Gurevitch B, Artru AA, Shapira Y, Reichenthal E. Neurologic outcome with hemorrhagic hypotension after closed head trauma in rats: effect of early versus delayed conservative fluid therapy. J Trauma 1997;43:667-72.
  12. Gross D, Landau EH, Assalia A, Krausz MM. Is hypertonic saline resuscitation safe in ‘uncontrolled’ hemorrhagic shock. J Trauma 1988;28:751-6.
  13. Gross D, Landau EH, Klin B, Krausz MM. Quantitative measurement of bleeding following hypertonic saline therapy in ‘uncontrolled’ hemorrhagic shock. J Trauma 1989;29:79-83.
  14. Gross D, Landau EH, Klin B, Krausz MM. Treatment of uncontrolled hemorrhagic shock with hypertonic saline solution. Surg Gynecol Obstet 1990;170:106-12.
  15. Haizlip TM, Poole GV, Falzon AL. Initial resuscitation volume in uncontrolled hemorrhage: effects on organ function. Am Surg 1999;65:215-7.
  16. Kim S, Stezoski SW, Safar P, Capone A, Tisherman S. Hypothermia and minimal fluid resuscitation increases survival after uncontrolled hemorrhagic shock in rats. J Trauma 1997;42:213-22.
  17. Kowalenko T, Stern S, Dronen S, Wang X. Improved outcome with hypotensive resuscitation of uncontrolled hemorrhagic shock in a swine model. J Trauma 1992;33:349-53.
  18. Krausz MM, Kablan M, Rabinovici R, Klin B, Sherman Y, Gross D. Effect of injured vessel size on bleeding following hypertonic saline infusion in uncontrolled hemorrhagic shock in anesthetised rats. Circulatory Shock 1991;35:9-13.
  19. Krausz MM, Horn Y, Gross D. The combined effect of small volume hypertonic saline and normal saline solutions in uncontrolled hemorrhagic shock. Surg Gynecol Obstet 1992;174:363-8.
  20. Krausz MM, Landau EH, Klin B, Gross D. Hypertonic saline treatment of uncontrolled hemorrhagic shock at different periods from bleeding. Arch Surg 1992; 127:93-6.
  21. Krausz MM, Bar-Ziv M, Rabinovici R, Gross D. "Scoop and run" or stabilize hemorrhagic shock with normal saline or small-volume hypertonic saline? J Trauma 1992;33:6-10.
  22. Krausz MM, David M, Amstislavsky T. Hypertonic saline treatment of hemorrhagic shock in awake rats. Shock 1994;2:267-70.
  23. Krausz MM, Amstislavsky T. Hypertonic sodium acetate treatment of hemorrhagic shock in awake rats. Shock 1995;4:56-60.
  24. Krausz MM, Bashenko Y, Hirsh M. Crystalloid or colloid resuscitation of uncontrolled hemorrhagic shock after moderate splenic injury. Shock 2000;13:230-5.
  25. Leppaniemi A, Soltero R, Burris D, Pikoulis E, Ratigan J, Waasdorp C, et al. Early resuscitation with low volume polyDCLHb is effective in the treatment of shock induced by penetrating vascular injury. J Trauma 1996;40:242-8.
  26. Leppaniemi A, Soltero R, Burris D, Pikoulis E, Waasdorp C, Ratigan J, et al. Fluid resuscitation in a model of uncontrolled hemorrhage: too much too early, or too little too late? J Surg Res 1996;63:413-8.
  27. Marshall HP, Capone A, Courcoulas AP, Harbrecht BG, Billiar TR, Udekwu AO, et al. Effects of hemodilution on long-term survival in uncontrolled hemorrhage shock model in rats. J Trauma 1997;43:673-9.
  28. Matsuoka T, Hildreth J, Wisner DH. Uncontrolled hemorrhage from parenchymal injury: is resuscitation helpful? J Trauma 1996;40:915-22.
  29. Owens TM, Watson WC, Prough DS, Uchida T, Kramer GC. Limiting initial resuscitation of uncontrolled hemorrhage reduces internal bleeding and subsequent volume requirements. J Trauma 1995;39:200-7.
  30. Rabinovici R, Gross D, Krausz MM. Infusion of small volume of 7.5 per cent sodium chloride in 6.0 per cent dextran 70 for the treatment of uncontrolled hemorrhagic shock. Surg Gynecol Obstet 1989;169:137-42.
  31. Rabinovici R, Krausz MM, Feuerstein G. Control of bleeding is essential for a successful treatment of hemorrhagic shock with 7.5 per cent sodium chloride solution. Surg Gynecol Obstet 1991;173:98-106.
  32. Riddez L, Johnson L, Hahn RG. Central and regional hemodynamics during crystalloid fluid therapy after uncontrolled intra-abdominal bleeding. J Trauma 1998;44:433-9.
  33. Sakles JC, Sena MJ, Knight DA, Davis JM. Effect of immediate fluid resuscitation on the rate, volume and duration of pulmonary vascular hemorrhage in a sheep model of penetrating thoracic trauma. Ann Emerg Med 1997;29:392-9.
  34. Selby JB, Mathis JE, Berry CF, Hagedorn FN, Illner HP, Shires GT. Effects of isotonic saline solution resuscitation on blood coagulation in uncontrolled hemorrhage. Surgery 1996;119:528-33.
  35. Silbergleit R, Satz W, McNamara RM, Lee DC, Schoffstall JM. Effect of permissive hypotension in continuous uncontrolled intra-abdominal hemorrhage. Acad Emerg Med 1996;3:922-6.
  36. Sindlinger JF, Soucy DM, Greene SP, Barber AE, Illner H, Shires GT. The effects of isotonic saline volume resuscitation in uncontrolled hemorrhage. Surg Gynecol Obstet 1993;177:545-50.
  37. Solomonov E, Hirsh M, Yahiya A, Krausz M. The effect of vigorous fluid resuscitation in uncontrolled hemorrhagic shock after massive splenic injury. Crit Care Med 2000;28:749-54.
  38. Soucy DM, Rudé, Hsia WC, Hagedorn FN, Illner H, Shires GT. The effects of varying fluid volume and rate of resuscitation during uncontrolled hemorrhage. J Trauma 1999;46:209-14.
  39. Soucy DM, Sindlinger JF, Greene SP, Barber AE, Illner HP, Shires GT. Isotonic saline resuscitation in uncontrolled hemorrhage under various anesthetic conditions. Ann Surg 1995;222:89-93.
  40. Stern SA, Dronen SC, Birrer P, Wang X. Effect of blood pressure on hemorrhage volume and survival in a near fatal hemorrhage model incorporating a vascular injury. Ann Emerg Med 1993;22:155-63.
  41. Stern SA, Dronen SC, Wang X. Multiple resuscitation regimens in a near-fatal porcine aortic injury hemorrhage model. Acad Emerg Med 1995;2:89-97.
  42. Stern SA, Zink BJ, Mertz M, Wang X, Dronen SC. Effect of initially limited resuscitation in a combined model of fluid-percussion brain injury and severe uncontrolled hemorrhagic shock. J Neurosurg 2000;93:305-14.
  43. Talmor D, Merkind V, Artru AA, Shapiro O, Geva D, Roytblat L, et al. Treatment to support blood pressure increases bleeding and/or decreases survival in a rat model of closed head trauma combined with uncontrolled hemorrhage. Anesth Analg 1999;89:950-6.


Posted as supplied by author

Details of 44 included trials of fluid replacement in animal models of uncontrolled haemorrhage
 

Study ID

Allocation methodAnimal modelInterventionOutcomesMortality results
Large animals (pigs and sheep)
Alspaugh 2000 USANot specified19 anaesthetised swineAnimals randomly assigned to two groupsDeath within 2 hours 

Swine of either gender averaging 50kg in body weight faster overnight but allowed free access to water. Model of uncontrolled haemorrhage produced by inflicting splenic laceration and cryogenic brain injury.

1. Pre-hospital resuscitation with Ringer’s Lactate1. Pre-hospital 3/9
2. Delayed resuscitation until after control of haemorrhage2. Delayed resuscitation 4/10
Bickell 1992 USANot specified24 immature Yorkshire swineAnimals divided into three groups:Death within 2 hours 

Following splenectomy a stainless steel wire was placed in the infrarenal aorta. The wire was pulled, producing a 5-mm aortotomy and spontaneous intraperitoneal haemorrhage.

1. Untreated group1. Untreated group 0/8
2. Treated group: 4mL/kg mixture of IV 7.5% NaCl and 6% Dextran-70 over one minute2. 7.5% NaCl and 6% Dextran-70 group 5/8
3. Treated group: 80 ml/kg lactated Ringer’s solution intravenously3. Lactated Ringer’s 8/8
Dronen 1993 USANot specified17 three to four month old Yorkshire swineAnimals were randomised into two groups:Death within 1 hour 

Immature swine were instrumented and subjected to severe blood loss (40 to 46 mL/kg), when the MAP was decreased to 30 mm Hg, a 4mm tear was created in the infra-renal aorta, allowing free intra-peritoneal bleeding.

1. No resuscitation1. No resuscitation 7/8
2. Resuscitation with normal saline infused at a rate of 6 mL/kg/min followed by shed blood at a rate of 2mL/kg/min infused to maintain a MAP of 80 mm Hg.2. Resuscitation 7/9
Kowalenko 1992 USANot specified24 immature swineAnimals were randomly divided into three groups:Death within 1 hour 

Pre-resuscitative haemorrhage is accurately controlled from a femoral artery catheter. Once animal reaches a mean arterial pressure of 30mm Hg a 4-mm aortic tear is inflicted, allowing free intra-peritoneal haemorrhage.

1. No fluids1. No fluids 7/8
2. Saline infusion at 6mL/kg/min to reach MAP 40mmHg2. MAP 40mmHg 1/8
3. Saline infusion at 6mL/kg/min to reach MAP 80mmHg3. MAP 80mmHg 5/8
Owens 1995 USANot specified20 immature Yorkshire swineAnimals were randomised into three groups:Death within 2 hours 

Swine were anaesthetised, arterial and venous catheters were inserted. 25-mL/kg blood was withdrawn during a 30 minute controlled haemorrhage, followed by a 20 minute uncontrolled haemorrhage from a 5mm aortotomy.

1. No resuscitation1. No resuscitation 1/6
2. Standard resuscitation: Lactated Ringer’s infused to achieve and maintain 100% baseline cardiac index for 20 minutes2. Standard resuscitation 1/6
3. Limited pre-hospital resuscitation: Lactated Ringer’s infused to achieve and maintain 60% baseline cardiac index for 20 minutes In the intra-operative phase intra-operative resuscitation was continued for 120 minutes using lactated Ringers to achieve 80% baseline CI.3. Limited pre-hospital resuscitation: 0/8
Riddez 1998 SwedenNot specified32 swineAnimals were randomised into four groups:Death within 1 hour 

Inducing a 5mm long laceration in the infra-renal aorta induced uncontrolled heamorrhagic shock.

1. No fluid resuscitation1. No fluid resuscitation 4/8
2. Ringer’s solution in about the same amount as the expected blood loss per hour (1:1) over 2 hours2. Ringer’s solution (1:1) 2/8
3. Ringer’s solution in a ratio 2:1 of the expected blood loss over 2 hours3. Ringer’s solution (2:1) 2/8
4. Ringer’s solution in a ration 3:1 of the expected blood loss over 2 hours4. Ringer’s solution (3:1) 4/8
Sakles 1997 USANot specified16 adult sheepAnimals were randomly divided into two groups:Death within 2 hours 

Sheep were anaesthetised and lacerating a branch of the pulmonary vein through an antero-lateral thoracotomy induced uncontrolled haemorrhage.

1. No resuscitation1. No resuscitation 1/8
2. Immediate resuscitation: 30 mL/kg Lactated Ringer’s solution over a period of 10 minutes, repeated to achieve normotension.2. Immediate resuscitation 1/8
Silbergleit 1996 USANot specified10 swineAnimals were randomly divided into two groups:Death within 1 hour 

Animals were anaesthetised and uncontrolled continuous haemorrhage was induced via catheters in the femoral vessels.

1. No fluid resuscitation1. No fluid resuscitation 3/5
2. Fluid resuscitation: 80mL/kg Lactated Ringer’s during a resuscitation phase between 10 and 20 minutes post injury.2. Fluid resuscitation 4/5
Stern 1993 USAAlternation27 immature Yorkshire swineAnimals were resuscitated with a saline infusion at 6mL/kg/min as needed to maintain the desired endpoints: Death within 1 hour 

Near-fatal porcine aortic injury haemorrhage model. Pre-resuscitative haemorrhage is accurately controlled from a femoral artery catheter. Once animal reaches a pre-determined physiologic end point, aortic tear is inflicted, allowing free intra-peritoneal haemorrhage

1. MAP 401. MAP 40 1/9
2. MAP 602. MAP 60 2/9
3. MAP 803. MAP 80 7/9
After 30 minutes or a total saline resuscitation 90 mL/kg, the resuscitation fluid was changed to shed blood infused 2mL/kg/min as needed to maintain the desired MAP.
Stern 1995 USAAlternation54 immature Yorkshire swineAnimals were divided into three groups:Death within 1 hour 

Near-fatal porcine aortic injury haemorrhage model. Pre-resuscitative haemorrhage is accurately controlled from a femoral artery catheter. Once animal reaches a pre-determined physiologic end point, aortic tear is inflicted, allowing free intra-peritoneal haemorrhage.

1. MAP 401. MAP 40 2/18
2. MAP 602. MAP 60 3/18
3. MAP 80 mm Hg3. MAP 80 14/18
Resuscitation fluid was either shed blood followed by normal saline or normal saline followed by shed blood.
Stern 2000 USANot specified24 swineAnimals were randomly assigned to one of three groups.Death within 150 minutes 

Each swine underwent fluid percussion brain injury and uncontrolled haemorrhage to a mean arterial pressure of 30mm Hg in the presence of a 4mm aortic tear.

1. No resuscitation1. no resuscitation 6/6
2. MAP 60 mm Hg2. MAP 60 mm Hg 1/9
3. MAP 80 mm Hg3. MAP 80 mm Hg 4/9
Small animals (rats)
Bilynskyj 1992 BrazilNot specified120 male Wistar ratsAnimals were divided into four anaesthetic groups and each of these were divided into two groups:Deaths within 4 hours 

Uncontrolled haemorrhage was induced by 12% or 50% tail resection

1. No fluid resuscitation1. No fluid resuscitation 9/60
2. Hypertonic saline (7.5%) 4mL/kg IV. 15 minutes from start of bleeding.2. Hypertonic saline 13/60
Burris 1999 USANot specified61 male Sprague-Dawley ratsFluids infused at 2 mL/Kg per minute were turned off or on to maintain a mean arterial pressure of 40, 80, or 100 mm Hg in six groups:Death within 70 minutes 

After instrumentation the heamodynamically stable but lightly anaesthetised rats were subjected to a vascular injury leading to uncontrolled haemorrhagic shock by piercing the infra-renal aorta with a 25-guage needle, creating two standard sized holes one each side of the aorta.

1. No fluid1. No fluid 11/11
2. Lactated Ringer’s MAP 1002. Ringer’s (MAP 100) 6/9
3. Lactated Ringer’s MAP 803. Ringer’s (MAP 80) 2/11
4. Lactated Ringer’s MAP 404. Ringer’s (MAP 40) 7/10
5. Hypertonic NaCl/hetastarch (MAP 80)5. NaCl/hetastarch (MAP 80) 8/11
6. Hypertonic NaCl/hetastarch (MAP 40)6. NaCl/hetastarch (MAP 40) 3/9
Capone 1995a USA*Randomised in blocks of four, allocation concealment not specified40 male Sprague-Dawley ratsExperimental design consisted of three phases: Pre-hospital phase: from insult to haemostasis 60 minutes later. During this phase uncontrolled haemorrhagic shock was produced so that different fluid resuscitation regimens could be tested. Hospital phase: started with haemostasis and continued for another 120 minutes, with unrestricted fluid resuscitation, including infusion of the donor blood to Hct 30% plus lactated Ringer’s solution to achieve normotension. Death within 3 days 

Uncontrolled haemorrhagic shock produced by a preliminary bleed (3 mL/100g) followed by 75% tail amputation.

Observation phase extended from the end of the hospital phase to 3 days to evaluate outcome. 

1. untreated controls

 

2. no pre-hospital fluid

2. no fluid 9/10
3. LR pre-hospital to maintain MAP at 40 mm HG3. LR pre-hospital (MAP 40) 4/10
4. LR pre-hospital to maintain MAP at 80 mm HG4. LR pre-hospital (MAP 80) 10/10
Group 1 not resuscitated in hospital phase is excluded.
Capone 1995b USANot specified40 male Sprague-Dawley ratsExperimental design consisted of three phases: a ‘pre-hospital phase’ (90 minutes of uncontrolled bleeding with or without Lactated Ringer’s solution) followed by a ‘hospital phase’ (60 minutes including control of bleeding and fluid resuscitation including blood) Death within 3 days 

Haemorrhage induced by an oblique sterile tail amputation of 75% its length, as measured from the tip.

1. untreated controls 

2. no pre-hospital fluid

2. no pre-hospital fluid 1/10
3. LR pre-hospital to maintain MAP at 40 mm HG3: LR pre-hospital (MAP 40) 0/10
4. LR pre-hospital to maintain MAP at 80 mm HG4. LR pre-hospital (MAP 80) 3/10
Groups 2,3 and 4 only were resuscitated in the hospital phase. Group 1 therefore not included.
Capone 1995c USA*Not specified20 male Sprague-Dawley ratsExperimental design consisted of three phases:Death within 3 days 

Volume controlled haemorrhage of 3mL/100g over 15 minutes followed by uncontrolled haemorrhage induced by an oblique sterile tail amputation of 75% its length, as measured from the tip.

Pre-hospital phase: from insult to haemostasis 90 minutes later. During this phase uncontrolled haemorrhagic shock was produced so that different fluid resuscitation regimens could be tested. 

Hospital phase: started with haemostasis and continued for another 60 minutes, with unrestricted fluid resuscitation, including infusion of the donor blood to Hct 30% plus lactated Ringer’s solution to achieve normotension.

 

Observation phase extended from the end of the hospital phase to 3 days to evaluated outcome.

 

1. no fluid resuscitation in either phase

1. no resuscitation 10/10
2. no resuscitation in pre-hospital phase, then in hospital phase all out fluid resuscitation as above.2. hospital resuscitation 9/10
Craig 1994 USANot specified45 male Sprague-Dawley ratsAnimals randomly divided into five groups:Death within 3 hours 

Rats were anaesthetised and a femoral artery and vein were cannulated for blood pressure monitoring and fluid infusion. Through a mid-line abdominal incision the distal ileocolic artery and vein were cut and allowed to bleed freely into the abdominal cavity. The abdomen was closed and the animals were randomised into five groups.

1. no resuscitation1. no resuscitation 2/9
2. small volume lactated Ringer’s solution2. small volume lactated Ringer’s solution 3/9
3. large volume lactated Ringer’s solution3. large volume lactated Ringer’s solution 4/9
4. small volume hetastarch4. small volume hetastarch 8/9
5. large volume hetastarch5. large volume hetastarch 4/9
Elgjo 1996 NorwayNot specified39 male Wistar-Kyoto ratsAnimals in each group were randomised into two groups:Death within 4 hoursArterial haemorrhage
Hypotension was induced by controlled withdrawal of blood until MAP reached 50 mm Hg. After 5 min subjects were randomised into two groups for uncontrolled haemorrhage: (1) arterial haemorrhage – the abdominal aorta puncture with a 21,22, or 23 gauge hypodermic needle; (2) venous haemorrhage – inferior caval vein puncture with a 18 or 19 gauge hypodermic needle.1. No treatment1. No treatment: 5/12
2. Saline 8.0% 2mL/kg IV at 0.4mL/min.2. Saline 8.0%: 6/10
Venous haemorrhage
1. No treatment: 0/7
2. Saline 8.0%: 1/10
Feldman 1997 IsraelNot specified56 male Sprague-Dawley ratsRandomly allocated to early or late fluid resuscitation with warmed lactated Ringer’s solution. Volume infused was three times the total amount of blood lost.Death within 2 hoursNo closed head injury
Halothane anaesthesia and divided into groups with or without closed head trauma. Head trauma was delivered to the skull over the frontal portion of the left cerebral hemisphere by a weight drop device. The 30 rats that survived were head injury were randomly divided into groups. Haemorrhagic hypotension was produced by 12% tail resection.1. Early resuscitation: IV fluids started 1.25 hours after injury.1. Early resuscitation 0/10
2. Delayed resuscitation: IV fluids started 2 hours after injury.2. Delayed resuscitation 0/10
Closed head injury
1. Early resuscitation 3/10
2. Delayed resuscitation 3/10
Greene 1998 USANot specified63 female Sprague-Dawley ratsRats were randomly divided into three groups:Death within 6 hours 

The day before the study the animals were cannulated through the jugular vein. Under light ether anaesthesia the rats were restrained and haemorrhage was initiated by a 75% tail resection with a guillotine.

1. not resuscitated1. not resuscitated 16/21
2. isotonic saline 40 mL/kg2. isotonic saline 40 mL/kg 15/21
3. isotonic saline 80 mL/kg

Fluid resuscitation was initiated 15 minutes after tail resection and given over a period of 4 minutes.

3. isotonic saline 80 mL/kg 5/21
Gross 1988 IsraelNot specified36 male Hebrew University ratsAnimals were divided into three groupsDeath within 3 hours 

The rats were anaesthetised and a mid-line laparotomy was performed. The ileocolic artery was identified and three of its major branches were incised longitudinally to induce uncontrolled intra-abdominal haemorrhage.

1. No resuscitation1. No resuscitation 2/9
2. IV 0.9% saline 5mL/kg at a rate of 0.4 ml/min2. IV 0.9% saline 3/9
3. IV 7.5% saline 5mL/kg injected intravenously3. IV 7.5% saline 17/18
Gross 1989 IsraelNot specified51 male Hebrew University ratsAnimals were divided into three groupsDeath within 3 hours 

The rats were anaesthetised and uncontrolled haemorrhagic shock was induced by sharp resection of 10% of the terminal portion of the tail.

1. No resuscitation1. No resuscitation 3/15
2. After 5 minutes, IV infusion of 0.9% saline 5mL/kg at a rate of 0.4 ml/min.2. IV 0.9% saline 1/14
3. After 5 minutes, IV infusion of 7.5% saline 5mL/kg injected intravenously3. IV 7.5% saline 16/22
Gross 1990 IsraelNot specified94 male Hebrew University ratsRats in each of the two groups were divided into six groups:Death within 2 hoursAbdomen closed
The rats were anaesthetised and a mid-line laparotomy was performed. The ileocolic artery was identified and three of its major branches were incised longitudinally to induce uncontrolled intra-abdominal haemorrhage. The rats were divided into two groups according to whether or not the abdomen was closed after induction of haemorrhage.1. Untreated1. Untreated 2/5
2. 5mL/kg 7.5% NaCl after five minutes2. 5mL/kg 7.5% NaCl after five minutes 12/14
3. 5mL/kg 7.5% NaCl after 15 minutes3. 5mL/kg 7.5% NaCl after 15 minutes 7/8
4. 15mL/kg 7.5% NaCl after 30 minutes4. 15mL/kg 7.5% NaCl after 30 minutes 5/9
5. 5mL/kg 7.5% NaCl after 60 minutes5. 5mL/kg 7.5% NaCl after 60 minutes 5/9
6. 5mL/kg 7.5% NaCl after 120 minutes6. 5mL/kg 7.5% NaCl after 120 minutes 7/9
Abdomen open
1. Untreated 0/5
2. 5mL/kg 7.5% NaCl after five minutes 9/9
3. 5mL/kg 7.5% NaCl after 15 minutes 1/6
4. 15mL/kg 7.5% NaCl after 30 minutes 1/6
5. 5mL/kg 7.5% NaCl after 60 minutes 2/8
6. 5mL/kg 7.5% NaCl after 120 minutes 1/6
Haizlip 1999 USANot specified30 male ratsAnimals were randomised into three groups:Death within 3 hours 

Uncontrolled intra-peritoneal haemorrhage was induced by division of the distal branches of the ileocolic artery and vein.

1. No fluid1. No fluid 1/10
2. 0.5 mL LR every 5 min if MAP less than 80 mm Hg2. 0.5mL LR 4/10
3. 2.0 mL LR every 5 min if MAP less than 80 mm Hg3. 2.0mL LR 0/10
Kim 1997 USANot specified45 rats (5 excluded due to catheter insertion problems)Animals were randomised into four groups:Death within 72 hours 

Following an initial volume controlled haemorrhage (3mL/100g), uncontrolled haemorrhagic shock was induced by 75% tail resection.

Normothermia (37.5C)Normothermia (37.5C)
1. no fluid resuscitation1. no resuscitation 10/10
2. Lactated Ringer’s to maintain MAP 40mm Hg2. MAP 40mm Hg 9/10
Hypothermia (30C)Hypothermia (30C)
1. no fluid resuscitation1. no resuscitation 7/10
2. Lactated Ringer’s to maintain MAP 40mm Hg2. MAP 40mm Hg 3/10
Krausz 1991 IsraelNot specified37 male Hebrew University ratsAnimals were randomly divided into four groupsDeath within 4 hours 

Either 8% or 50% tail resection induced uncontrolled haemorrhagic shock.

8% tail resection8% tail resection
1. no resuscitation1. no resuscitation 0/8
2. saline 7.5% 5mL/kg2. saline 7.5% 5mL/kg 0/8
50% tail resection50% tail resection
1. no resuscitation1. no resuscitation 0/9
2. saline 7.5% 5mL/kg2. saline 7.5% 5mL/kg 7/12
Krausz 1992a IsraelNot specified33 male Hebrew University ratsAnimals randomly divided into four groups:Death within 4 hours 

Uncontrolled haemorrhagic shock was induced by resection of 12% of the terminal portion of the tail.

1. Untreated1. Untreated 2/9
2. 41.5 mL/kg 0.9% NaCl after 15 minutes2. 41.5 mL/kg 0.9% NaCl after 15 minutes 0/8
3. 5 mL/kg 7.5% NaCl after 15 minutes3. 5 mL/kg 7.5% NaCl after 15 minutes 5/7
4. 41.5 mL/kg 0.9%NaCl and 5mL/kg 7.5% NaCl after 15 minutes4. 41.5 mL/kg 0.9%NaCl and 5mL/kg 7.5% NaCl after 15 minutes 1/9
Krausz 1992b IsraelNot specified37 male Hebrew University ratsAnimals were randomly divided into five groups giving 5mL/kg 7.5% NaCl after:Death within 4 hours 

Uncontrolled haemorrhagic shock was induced by 10% tail resection.

1. untreated1. Untreated 2/15
2. saline after 5 min2. saline after 5 min 12/15
3. saline after 15 min3. saline after 15 min 8/15
4. saline after 30 min4. saline after 30 min 0/10
5. saline after 60 min5. saline after 60 min 0/10
6. saline after 120 min6. saline after 120 min 1/10
Krausz 1992c IsraelNot specified25 male Hebrew University ratsAnimals were randomly divided into three groups:Death within 4 hours 

Uncontrolled haemorrhagic shock was induced by 12% tail resection.

1. Untreated1. Untreated 4/13
2. 41.5mL/kg 0.9% NaCl2. 0.9% NaCl 2/6
3. 5.0mL/kg 7.5% NaCl3. 7.5% NaCl 6/6
Krausz 1994 IsraelNot specified16 male Hebrew University ratsAnimals randomly divided into two groups:Death within 4 hours 

Uncontrolled haemorrhagic shock was induced by transcutaneous tear of two branches of the ileocolic artery.

1. Untreated1. Untreated 3/8
2. Saline (7.5%) 5 mL/kg after 10 minutes2. Saline 7.5% 6/8
Krausz 1995 IsraelNot specified32 male Hebrew University ratsAnimals randomly divided into four groups:Death within 4 hours 

Uncontrolled haemorrhagic shock was induced by transcutaneous tear of two branches of the ileocolic artery.

1. Untreated1. Untreated 2/8
2. 5 mL/kg 7.5% saline after five minutes2. 5 mL/kg 7.5% saline after five min 6/8
3. 5 mL/kg 9.2% sodium acetate after 5 minutes3. 5 mL/kg 9.2% sodium acetate after five min 4/8
4. 41.5 mL/kg 0.9% saline infused in 15 minutes4. 41.5 mL/kg 0.9% saline infused in 15 min 2/8
Krausz 2000 IsraelNot specified50 male Sprague-Dawley ratsAnimals randomly divided into five groups:Death within 4 hoursOnly cumulative death data reported.
Uncontrolled haemorrhagic shock was induced by moderate splenic injury.1. Untreated
2. 41.5mL/kg Lactated Ringer’s after 10min
3. 5 mL/kg 7.5% NaCl after 10 min
4. 7.5 mL/kg hydroxyethyl starch 6% after 10 min

5. 15mL/kg hydroxyethyl starch 6% within 10 min

Leppaniemi 1996a USANot specified40 male Sprague-Dawley ratsAnimals were randomly divided into three groups:Death within 6 hours 

Uncontrolled haemorrhagic shock was induced by a 25-gauge needle puncture to the infra-renal aorta.

1. No resuscitation1. No resuscitation 6/8
2. Lactated Ringer’s 60 mL/kg at 1.5 mL/min2. Lactated Ringer’s 60 mL/kg at 1.5 mL/min 2/8
3. 7.5% saline 5 mL/kg at 1.5 mL/min3. 7.5% saline 5 mL/kg at 1.5 mL/min 6/8
Leppaniemi1996b USANot specified40 Male Sprague-Dawley ratsAnimals were randomly divided into six groups:Death within 3 hours 

Uncontrolled haemorrhagic shock was induced in anaesthetised animals by a 25-gauge needle puncture to the infra-renal aorta.

1. No resuscitation1. No resuscitation 7/9
2. Lactated Ringer’s 60 mL/kg at 1.5 mL/min and given at 2.5 minutes2. Lactated Ringer’s 60 mL/kg at 1.5 mL/min and given at 2.5 minutes 2/6
3. Lactated Ringer’s 60 mL/kg at 1.5 L/min and given at 5 minutes3. Lactated Ringer’s 60 mL/kg at 1.5 mL/min and given at 5 minutes 1/6
4. Lactated Ringer’s 60 mL/kg at 1.5 mL/min and given at 10 minutes4. Lactated Ringer’s 60 mL/kg at 1.5 mL/min and given at 10 minutes 1/6
5. Lactated Ringer’s 60 mL/kg at 3.0 mL/min and given at 5 minutes5. Lactated Ringer’s 60 mL/kg at 3.0 mL/min and given at 5 minutes 5/6
6. Lactated Ringer’s 60 mL/kg at 3.0 mL/min and given at 10 minutes6. Lactated Ringer’s 60 mL/kg at 3.0 mL/min and given at 10 minutes 0/6
Marshall 1997 USANot specified32 male Sprague-Dawley ratsAnimals were randomly divided into four groups:Death within 3 days 

Uncontrolled haemorrhagic shock was induced by preliminary bleed of 3mL/100g followed by 75% tail amputation. Experiment comprised three phases: (1) pre-hospital phase with uncontrolled bleeding and resuscitation to either 40 or 80 mm Hg; (2) hospital phase with control of bleeding and resuscitation to a mean arterial pressure of more than 80 mm Hg; (3) a 3-day observation phase.

1. MAP 40 mm Hg with lactated Ringer’s1. MAP 40 mm (LR) 2/8
2. MAP 40 mm Hg with Lactated Ringer’s and blood2. MAP 40 mm Hg (LR+B) 1/8
3. MAP 80 mm Hg with Lactated Ringer’s3. MAP 80 mm Hg (LR) 8/8
4. MAP 80 mm Hg with Lactated Ringer’s and blood4. MAP 80 mm Hg (LR+B) 0/8
Matsuoka 1996 USANot specified120 adult male Sprague-Dawley ratsAnimals were randomised into four groups:Death within 4 hours 

Creating a standardised liver injury at the beginning of the shock period induced uncontrolled haemorrhage.

1. No resuscitation1. No resuscitation 15/30
A midline celiotomy was performed and about 65% of the median and left lateral lobes of the liver were removed.2. Lactated Ringer’s solution 4mL/kg2. Lactated Ringer’s solution 4mL/kg 14/30
3. Lactated Ringer’s solution 24mL/kg3. Lactated Ringer’s solution 24mL/kg 12/30
4. 7.5% saline 4 mL/kg4. 7.5% saline 4 mL/kg 3/30
Rabinovici 1989 IsraelNot specified50 male Hebrew University ratsAnimals were randomly divided into five groups:Death within 4 hours 

Rats were anaesthetised and uncontrolled haemorrhage was induced by sharp resection of 10% of the terminal portion of the tail.

1. No treatment1. No treatment 1/10
2. After 5 minutes, 5mL/kg 0.9% saline at 0.4 mL/min2. After 5 minutes, 5mL/kg 0.9% saline at 0.4 mL/min 2/10
3. After 5 minutes, 5mL/kg 6% dextran 70 at 0.4 mL/min3. After 5 minutes, 5mL/kg 6% dextran 70 at 0.4 mL/min 5/10
4. After 5 minutes, 5mL/kg 7.5% saline was infused4. After 5 minutes, 5mL/kg 7.5% saline was infused 6/10
5. After 5 minutes, 5mL/kg 7.5% saline in 6% dextran 70 was infused5. After 5 minutes, 5mL/kg 7.5% saline in 6% dextran 70 was infused 6/10
Rabinovici 1991 USANot specified21 male Sprague-Dawley ratsAnimals were randomly divided into three groups:Time to death data only hoursDeath data not reported.
Rats were anaesthetised and uncontrolled haemorrhage was induced by sharp resection of 15% of the terminal portion of the tail.1. No treatment
2. Saline 7.5% 5mL/kg fifteen min after tail resection
3. Saline 7.5% 41.5mL/kg fifteen min after tail resection
Selby 1996 USANot specified24 Sprague-Dawley ratsAnimals were randomly divided into four groups:Death within 3 hoursDeath data not reported.
Uncontrolled haemorrhage was induced by sharp 75% tail resection.1. No resuscitation
2. isotonic saline 40mL/kg in 4 minutes
3. isotonic saline 80mL/kg in 4 minutes
4. isotonic saline 80mL/kg in 1 minutes
Sindlinger 1993 USANot specified45 female Sprague-Dawley ratsAnimals were randomly divided into three groups:Death within 6 hours. 

Animals were anaesthetised with pentobarbital and uncontrolled haemorrhage was induced by 75% tail resection with a guillotine.

1. No resuscitation1. No resuscitation: 11/15
2. saline 0.9% 40 mL/kg over a four minute interval 15 min after haemorrhage2. saline 40 mL/kg: 6/15
3. saline 0.9% 80 mL/kg over a four minute interval 15 min after haemorrhage3. saline 80 mL/kg: 8/15
Solomonov 2000 IsraelNot specified45 adult Sprague-Dawley ratsAnimals were randomly divided into three groups:Death within one hour 

Creating a standardised massive splenic injury induced uncontrolled haemorrhagic shock by two transverse incisions in the rat’s spleen.

1. No resuscitation1. No resuscitation 2/15
2. Treated after 15 minutes with 41.5mL/kg 0.9% saline infused within 10 minutes.2. Saline 41.5mL/kg 5/15
3. Treated after 15 minutes with 5mL/kg

7.5% saline infused within 10 minutes.

3. Saline 5mL/kg 9/15
Soucy 1995 USANot specified135 female Sprague-Dawley ratsAnimals were divided into three groups: no anaesthesia, pentobarbital anaesthesia and droperidol and ketamine anaesthesia. Each for the groups was then randomly divided into three sub-groups:Death within 3 hours 

Uncontrolled haemorrhage was induced by 75% tail resection.

1. No resuscitationNo anaesthesia
2. isotonic saline 40ml/kg1.No resuscitation 14/15
3. isotonic saline 80mL/kg2. saline 40ml/kg 11/15
Each given 15 minutes after initiation of haemorrhage.3. saline 80mL/kg 5/15
Pentobarbital anaesthesia
1. No resuscitation 11/15
2. saline 40ml/kg 6/15
3. saline 80mL/kg 8/15
Droperidol and ketamine
1. No resuscitation 15/15
2. saline 40ml/kg 10/15
3. saline 80mL/kg 5/15
Soucy 1999 USANot specified43 female Sprague-Dawley ratsAnimals were randomised into five groups:Death within 3 hours 

Uncontrolled haemorrhage was induced by 75% tail resection.

1. No resuscitation1. No resuscitation 10/12
2. Moderate volume (80 mL/kg) Slow infusion (0.82 mL/min)2. Moderate/ Slow 4/6
3. Moderate volume (80 mL/kg) Fast infusion ( 4.4 mL/min)3. Moderate/Fast 4/10
4. High volume (283 mL/kg) Slow infusion (0.82 mL/min)4. High/Slow 7/8
5. High volume (283 mL/kg) Fast infusion (4.4 mL/min)5. High/Fast 5/7
Talmor 1999 USANot specified207 male Sprague-Dawley ratsAnimals were randomly assigned to head injury or no head injury groups.Death within 24 hours 

Rats were divided into groups with or without closed head injury. Uncontrolled haemorrhagic shock was induced 25% tail resection.

Closed head injuryClosed head injury
1. No resuscitation1. No resuscitation 3/11
2. saline 3mL per mL blood lost2. saline 3mL per mL blood lost 2/10
No closed head injuryNo closed head injury
1. No resuscitation1. No resuscitation 0/8
2. saline 3mL per mL blood lost2. saline 3mL per mL blood lost 1/9
Closed head injuryClosed head injury
1. Target MAP 701. Target MAP 70 6/14
2. Target MAP 802. Target MAP 80 7/15
3. Target MAP 903. Target MAP 90 0/0
No closed head injuryNo closed head injury
1. Target MAP 701. Target MAP 70 1/9
2. Target MAP 802. Target MAP 80 3/11
3. Target MAP 903. Target MAP 90 0/0

*Details of both trials were reported in the same paper.