mm Hypotensive resuscitation FROm animal study to clinical practice Dr YW Wong United Christian Hospital

Outline History of fluid resuscitation Clinical trial Guideline Animal studies Human studies Guideline Controversies Conclusion

Trauma Trauma had long been a major cause of preventable deaths worldwide. One-third of trauma deaths because the victims bleed to death within the first several hours

Lethal triad In the past, high volume resuscitation strategies was used to reverse haemorrhagic shock However, still a number of patient develop lethal triad and leads to mortality Acidosis, hypothermia, coagulopathy Can be due to the injury, or due to resuscitation

History of Fluid resuscitation Controlled hemorrhage animal models in 1950s. Wiggers insert a IV catheter, allow the animal to bleed and maintain a predetermined level of hypotension Fluid deficit was corrected with crystalloid 3 times the blood loss Lead to traditional fluid replacement regimen of 3:1 crystalloid: blood

Wiggers’ model may not be accurate Blood pressure is controlled by investigator by controlling the blood loss through the iv catheter

Aggressive fluid resuscitation Early aggressive fluid resuscitation was used routinely in Vietnam War in 1970s Coincidentally, ARDS was commonly described

1980s Uncontrolled haemorrhagic models were developed to simulate blunt trauma maximal vasoconstriction thrombus formation Animal study : Aggressive resuscitation with isotonic crystalloid Increase blood pressure and increase blood loss Did not reduce mortality

Hypotensive Resuscitation

Hypotensive Resuscitation In haemorrhagic shock patient, hypotension and vasoconstriction help to stalilized the clot Increasing the blood pressure places additional stress on formed clot Blood pressure greater than 90mmHg associated with higher risk of re-bleeding Hypotensive resuscitation aim at keeping the blood pressure low enough while maintaining perfusion of end organ.

Hypotensive Resuscitation Walter Cannon proposed it in 1918 “If the pressure is raised before the surgeon is ready to check any bleeding that may take place, blood that is sorely needed may be lost” The preventive treatment of wound shock JAMA 70:618-621 George Higginson Professor of Physiology Who invented the word ‘homeostasis’

MAP 40 MAP 80 MAP 0 By Aortotomy MAP 40mmHg group had better survival than MAP 80mmHg group Map 40mmHg group also had less blood loss

2003 Hypotensive resuscitation improved mortality compared to traditional resuscitation

How about Human Studies?

Prospective controlled trial Single centre Penetrating torso injury with SBP < 90mmHg Exclude: pregnant, age <16, revised trauma score 0, fatal gunshot to head, not requiring operation Immediate Resuscitation (309) traditional resuscitation with crystalloid Delayed Resuscitation (289) Withhold IV Fluid until arrival to operative theatre VS

Delayed resuscitation: Less fluid and packed cell given Delayed resuscitation: pre op Lower SBP Better Hb, plt, clotting profile

Delayed resuscitation: Improved survival (62% vs 70%) Shorter length of stay Delayed resuscitation: Trend of less ARDS

Randomized controlled trial Single centre Trauma patient with SBP <90mmHg Exclude: pregnant, CNS injury/ impaired consciousness, age >55, history of DM/ IHD Target SBP > 100mmHg (55) VS Target SBP 70mmHg (55) Titrating Crystalloid or blood product Fluid restriction to lower BP Until active bleeding was stopped

SBP 114 +-12 VS SBP 100 +- 17 Similar survival: 92.7%

Cochrane Review Timing and volume of fluid administration for patients with bleeding (2003) We found no evidence from randomized controlled trials for or against early or larger volume of intravenous fluid administration in uncontrolled haemorrhage. While increasing fluids will maintain blood pressure, it may also worsen bleeding by diluting clotting factors.

That was 10 years ago Few more studies published recently

Retrospective cohort study Single centre Including patient with emergent damage control laparotomy Exclude: age <18, pregnant, die on scene or during OT Normotenive group (282) VS Hypotensive group (108)

Hypotensive group: Better: Fluid: Survival: temp, heart rate, plt, INR, fibrinogen, pH, base value, lactate Fluid: Less fluid given (13.9L vs 5L) Less RBC, plasma, platelet transfusion Survival: 24hr survival ( 97% vs 88%) 30day survival ( 86% vs 76%)

Ongoing study

Target Intra-op MAP 50mmHg Target Intra-op MAP 65mmHg Ongoing RCT Single centre Trauma patients with SBP <90mmHg need laparotomy or thoracotomy Exclude: age >45, <14, pregnant, history of IHD/CVA, head injury Minimum blood pressure to trigger further resuscitation If spontaneously MAP higher than target, no further action A randomized trial is under way ay Baylor University looking at permissive hypotension Preliminary findings, published earlier this year in the Journal of Trauma, shows that targeting resuscitation to a mean arterial pressure of 50mmHg results in reduced intraoperative red blood cell and plasma transfusion less post operative coagulopathy higher 24Hr survival. Target Intra-op MAP 50mmHg Target Intra-op MAP 65mmHg VS

Survival MAP 50mmHg had better 24hr survival reduced transfuion requirement Less coagulopathy

So Which way is correct Consequences of aggressive fluid resuscitation and bursting the clot Consequences of hypotension and decreased organ prefusion

Different Parties have different practice

ATLS Everyone gets 2 liters of crystalloid initially Responders Transient responders  rebolus or blood for ongoing bleeding Non-responders blood for serious ongoing bleeding

NICE guideline Recommendation on trauma Adults and older children IV fluid should not be administered if radial pulse is present 250ml IV fluid should be given if pulse cannot be felt Burns, Blast injuries, Head injuries exception to permissive hypotension

US Army Stop bleeding 500ml fluid if If positive response, stop fluids No radial pulse or Decrease mental status If positive response, stop fluids

Something is still missing

Unsolved problems Concept of hypotensive resuscitation is clear But the definition is not! Different studies use different definition SBP? MAP? Limit crystaloid? Complete withhold or titrate against target BP?

Unsolved problems Application in concomitant head injury patient? Need to maintain CPP

Unsolved problems Application in concomitant head injury patient? Lack of human study on this area Animal study: Stern 2000 Swine model on uncontrolled haemorrhage and brain injury MAP 60 vs 80 Survival: MAP 60 better and MAP 80 Similar ICP and cerebral blood flow Draw back: no long term neurological outcome

Unsolved problems Duration of hypotensive resuscitation before irreversible damage Lack of consensus In Dutton’s studies Mean duration is 2.57 hour Similar survival between 2 group

Difficult area for research Heterogeneous definition of hypotensive resuscitation Heterogeneous group of trauma patients US: both penetrating and blunt trauma UK: most blunt trauma and head injury Ethical issue, difficult to recruit trauma patient Limited paper focus on this topic

Conclusion Aggressive fluid resuscitation in trauma case may not be totally beneficial Multiple animal studies demonstrate benefits of hypotensive resuscitation Equivocal result from human studies. Yet more recent studies demonstrate beneficial effect of hypotensive resuscitation Different parties had different practice worldwide Ongoing RCT may help to provide more evidence in near future

Thank You