Download INTRA-OPERATIVE HYPOTENSIVE RESUSCITATION FOR PATIENTS UNDERGOING

INTRA-OPERATIVE HYPOTENSIVE RESUSCITATION FOR PATIENTS UNDERGOING
LAPAROTOMY OR THORACOTOMY FOR TRAUMA: THE SAFETY PHASE OF A RANDOMIZED
PROSPECTIVE CLINICAL TRIAL
Introduction:
Trauma is the leading cause of mortality in young adults, and hemorrhagic shock is thought to be directly
responsible for one third of these deaths.1-3 Although the practice of high-volume administration has been
the standard of care in early trauma resuscitation for decades, a growing number of studies suggest this
may not be the ideal paradigm for fluid resuscitation. For patients with active bleeding, rapid restoration of
a normal blood pressure can lead directly to increased blood loss. Furthermore, administration of large
volumes of isotonic fluids can exacerbate the “lethal triad” of hypothermia, acidemia, and coagulopathy,
indirectly leading to further blood loss and can lead to other complications such as abdominal
compartment syndrome and ARDS as well.4-9 Human studies have repeatedly failed to show significant
improvement in mortality with the early, rapid administration of intravenous fluids 10-16, and several trials
have demonstrated worse outcomes when aggressive resuscitation is employed.17-20 A number of preclinical studies have shown improved survival in animals resuscitated to a lower blood pressure,21 as has
a randomized controlled clinical trial comparing low-volume fluid resuscitation to conventional methods for
trauma patients in the pre-hospital setting.17 The lack of evidence supporting the use of aggressive
resuscitation has led several consensus groups to recommend only limited use of intravenous fluids in the
pre-hospital setting and to encourage further research to establish the best strategy for resuscitation of
hemorrhagic shock for those patients who require surgical control of ongoing bleeding.22-24
To date, there have been no studies regarding intra-operative resuscitation goals for trauma patients in
hemorrhagic shock. However, human studies in the elective setting have shown a decrease in operative
blood loss when hypotension is deliberately induced intra-operatively. This field of operative management
is known as "hypotensive anesthesia". Hypotensive anesthesia has been found to be particularly useful
in cases where operative control of bleeding can be difficult, and may thus have implications for the acute
management of hemorrhagic shock. 25-29 Although the safety of hypotensive anesthesia has been
established in the elective setting—even in elderly patients26—theoretical safety concerns with regards to
hypotensive resuscitation in the emergency setting have not been addressed in clinical studies. With this
in mind, we designed a prospective randomized controlled trial which would allow us to evaluate the
effects of intra-operative hypotensive resuscitation in trauma patients with hemorrhagic shock. We herein
report our results from the safety phase of this trial.
Methods:
Approval for the study was obtained from the Baylor College of Medicine IRB prior to subject enrolment.
Patients undergoing laparotomy or thoracotomy for blunt and penetrating trauma that had at least one inhospital documented systolic blood pressure (SBP) less than or equal to 90 mm Hg and clinical suspicion
of hemorrhagic shock were enrolled under a waiver of informed consent for emergency research. Those
with a known history of cerebrovascular, cardiac or renal disease, pregnancy, possible head injury or age
greater than 45 years were excluded. Upon decision to go the OR, patients were randomized to one of
two groups for the management of intra-operative resuscitation: an experimental group (LMAP) with a
target minimum mean arterial pressure of 50 mm Hg, or a control group (HMAP) with a target minimum
mean arterial pressure of 65 mm Hg. Methods by which the target goals were met were left to the
discretion of the treating anesthesiologist. Before the operating room and in all other aspects of their care
the patients are treated as per standard of care. Patients were followed for 30 days post-operatively for
mortality and post-operative complications including stroke, myocardial infarction, acute renal failure,
hypotension requiring pressor support, coagulopathy, thrombocytopenia, and anemia. Statistical analysis
was performed using STATA® statistical software package, version 10.0 (StataCorp, College Station,
TX).
Results:
A total of 45 patients were enrolled: 22 in the LMAP group and 23 in the HMAP group. There were no
statistically significant differences at baseline with regards to injury severity scores, mechanism of injury,
presenting vitals, or demographics, with the exception of age (29.4 versus 36.1 years, respectively
(p=0.0078). Patients in the LMAP group tended to receive fewer intra-operative transfusions and lower
total volume of intra-operative fluids, although these differences did not reach statistical significance.
Patients in the HMAP group had a significantly shorter time until administration of first fluid or pressure
bolus (9.0 versus 20.3 minutes, p=0.0235). There were no statistically significant differences in other
intra-operative parameters between the two groups.
Overall 30-day survival was similar between the two groups, but patients in the LMAP group had
significantly fewer immediate post-operative deaths (0 in the LMAP group versus 5 in the HMAP group,
p=0.049). Both groups had similar rates of stroke, MI, acute renal failure, hypotension, coagulopathy,
thrombocytopenia, and anemia.
MAP=50
(n=22)
MAP=65
(n=23)
p-values
5 (22.7%)
8 (34.8%)
0.512
0 (0%)
5 (21.7%)
0.049
Acute MI
1 (4.5%)
0(0%)
1.000
Stroke
1 (4.5%)
0 (0%)
1.000
Renal Failure
2 (9.1%)
2 (8.7%)
1.000
Hypotension
4 (24%)
3 (18%)
1.000
Coagulopathy
14 (63.3%)
11(47.8%)
0.734
Thrombocytopenia
Anemia
8 (36.4%)
9 (40.9%)
4 (17.4%)
11 (47.8%)
0.307
0.641
Deaths at 30-days
Post-op deaths <24Hr
*Complication rates do not include patients who died <24Hr.
*Renal failure= creatinine >2.0 or need for hemodialysis
*Hypotension= any episode requiring vasopressor support
*Coagulopathy= INR >1.3 at any time
* Thrombocytopenia= Platelets <100k at any time
* Acute MI= elevated cardiac enzymes + EKG changes suggestive of AMI
* Stroke= Decreased mental status + imaging findings suggestive of
ischemia
*Anemia= Post-operative hemoglobin <10.0
*All p-values calculated using chi-squared or Fisher’s exact test, as
appropriate
One patient in the LMAP group sustained anoxic brain injury and evidence of acute MI. This patient was
included in the analysis on an intent-to-treat basis, although it should be noted that he arrived to the
hospital pulseless and had been hypoxic for an unknown period of time prior to arrival. Thus, it is difficult
to distinguish whether his post-operative complications were related directly to the hypotensive
resuscitation strategy or to pre-hospital anoxic insult. This patient later died after family decision to
withdraw care secondary to poor prognosis and vegetative neurologic status. None of the patients who
developed acute renal failure required hemodialysis at time of hospital discharge.
Discussion:
The concept of hypotensive resuscitation is not new. The first randomized controlled trial to study limited
fluid resuscitation for trauma in humans was conducted in 1999. This study demonstrated an increase in
survival among patients assigned to receive a lower fluid volume in the pre-hospital setting.17 A second
human study published in 2002 failed to demonstrate a significant difference in outcomes between
patients who were resuscitated to two different target blood pressures. However, this study was limited by
a heterogeneous sample population including a subset of patients with a lower injury burden. 16
Based upon the limited existing evidence, a consensus review published in the Emergency Medicine
Journal in 2002 recommended limited fluid administration in pre-hospital trauma victims, but
acknowledged that there is still lack of unequivocal data to clearly advocate one resuscitation strategy
over another.22 Likewise, the Institute of Medicine’s Committee on Fluid Resuscitation for Combat
Casualties has recommended an initial fluid bolus of no more than 250cc for the early management of
hemorrhagic shock.24 A Cochrane systematic review of the timing of fluid administration during ongoing
bleeding found evidence supporting hypotensive resuscitation, but concluded that “there is uncertainty
about the best time to give fluid and what volume of fluid should be given,” and that “more research is
needed” to definitively answer these questions. 23
Theoretical concerns regarding the safety of hypotensive resuscitation are based on the possible harmful
effects of decreased oxygen delivery to the various tissues of the body. Maintaining a blood pressure that
is too low could result in inadequate perfusion and subsequent organ failure, with potentially catastrophic
outcomes. On the other hand, critics of aggressive fluid resuscitation argue that maintaining a high or
“normal” blood pressure in the face of uncontrolled hemorrhagic shock can result in equally catastrophic
outcomes secondary to exsanguination and the “lethal triad” of hypothermia, acidemia, and coagulopathy.5,6 Thus, it would seem that establishment of a target mean arterial pressure for resuscitation that lies
somewhere in between these two extremes would be ideal—providing a pressure that is high enough to
maintain adequate perfusion but without resulting in excessive blood loss.
Research in animals has shown that “limited fluid resuscitation” in the face of ongoing bleeding results in
significantly improved survival than attempting to restore pre-injury baseline blood pressures.30 Indeed, a
myriad of animal and human studies support the use of hypotensive resuscitation in the setting of
uncontrolled hemorrhagic shock. To date, no studies have addressed the safety of intra-operative
hypotensive resuscitation in trauma patients in a prospective, randomized manner. Our results show that
patients randomized to the experimental (LMAP) group actually had significantly lower early postoperative mortality (p=0.049), lower 30-day mortality (not statistically significant) and similar complication
rates compared to the control (HMAP) group. These findings from the safety phase of our trial suggest
that a hypotensive resuscitation strategy for hemorrhagic shock can be successfully implemented in the
operative setting without increased risk of mortality or serious complications. Limitations of this study
include its small sample size and somewhat heterogeneous patient population, however the initial survival
differences and low rates of serious complications in both groups are encouraging. Further research is
necessary to better delineate the efficacy of hypotensive resuscitation in civilian trauma.
References:
1. Minino AM, Anderson RN, Fingerhut LA, Boudreault MA, Warner M. Deaths: Injuries, 2002. Natl
Vital Stat Rep 2006; 54 (10): 1-124.
2. Kung HC, Hoyert DL, Xu J, Murphy SL. Deaths: Final Data for 2005. Natl Vitsl Stat Rep 2008; 56
(10): 1-66.
3. Kauvar DS, Lefering R, Wade CE. Impact of Hemorrhage on Trauma Outcome: An Overview of
Epidemiology, Clinical Presentations, and Therapeutic Considerations. J Trauma. 2006;60:S3–
S11.
4. Balogh Z, McKinley BA, Cocanour CS, et al. Supranormal trauma resuscitation causes more
cases of abdominal compartment syndrome. Arch Surg 2003; 138: 637-42.
5. Tieu BH, Holcomb JB, Schreiber MA. Coagulopathy: Its Pathophysiology and Treatment in the
Injured Patient. World J Surg 2007 31: 1055–1064.
6. Rotondo MF, Zonies DH. The damage control sequence and underlying logic. Surg Clin N Am
1997; 77(4): 762-78.
7. Velmahos GC, Demetriades D, Shoemaker WC, et al. Endpoints of resuscitation of critically
injured patients: normal or supranormal? A prospective, randomized trial. Ann Surg 2000; 232:
409-18.
8. Cotton BA, Guy JS, Morris JA, Abumrad NN. The cellular, metabolic, and systemic
consequences of aggressive fluid resuscitation strategies. Shock 2006; 26(2): 115-21.
9. Cobb JP, Buchman TG, Karl IE, Hotchkiss RS. Molecular biology of multiple organ dysfunction
syndrome: injury, adaptation, and apoptosis. Surg Infec 2000; 1(3): 207-15.
10. Marr AB, Moore FA, Sailors RM, et al. Preload optimization using “starling curve” generation
during hemorrhagic shock resuscitation: can it be done? Shock 2004; 21: 300-5.
11. Aprahamian C, Thompson BM, Towne JB, et al. The effect of a paramedic system on mortality of
major open intra-abdominal vascular trauma. J Trauma 1983; 2#: 687-90.
12. Kaweski SM, Sise MJ, Virgilio RW. The effect of pre-hospital fluids on survival in trauma patients.
J Trauma 1990; 20:1215-8.
13. Turner J, Nichol J, Webber L, et al. A randomized controlled trial of prehospital intravenous fluid
replacement therapy in serious trauma. Health Technol Access 2000; 4:1-57.
14. Greaves MW, Hussein SH. Fluid resuscitation in pre-hospital trauma care: a consensus view. J
R Coll Surg Edinb 2002; 47: 451-7.
15. Dula DJ, Wood GC, Rejmer AR, et al. Use of prehospital fluids in hypotensive blunt trauma
patients. Prehosp Emerg Care 2002; 6:417-20.
16. Dutton RP, Mackenzie CF, Scalea TM. Hypotensive resuscitation during active hemorrhage:
impact on in-hospital mortality. J Trauma 2002; 52: 1141-6.
17. Bickell WH, Wall MJ, Pepe PE, et al. Immediate versus delayed fluid resuscitation for hypotensive
patients with penetrating torso injuries. N Engl J Med 1994; 331: 1105-9.
18. Puritt BA. Protection from excessive resuscitation: pushing the pendulum back. J Trauma 2000;
49: 567-8.
19. Navarrete-Navarro P, Ruiz-Bailén M, Rivera-Fernández R, et al. Acute respiratory distress
syndrome in trauma patients: ICU mortality and prediction factors. Intensive Care Med. 2000
Nov;26(11):1624-9.
20. Balogh Z, McKinley BA, Cocanour CS, et al. Supranormal trauma resuscitation causes more
cases of abdominal compartment syndrome. Arch Surg 2003; 138: 637-42.
21. Mapstone J, Roberts I, Evans P. Fluid Resuscitation Strategies: A Systematic Review of Animal
Trials. J Trauma. 2003;55:571–589.
22. Revell M, Porter K, Greaves I. Fluid resuscitation in prehospital trauma care: a consensus view.
Emerg Med J. 2002 Nov;19(6):494-8.
23. Kwan I, Bunn F, Roberts I. Timing and volume of fluid administration for patients with bleeding
(Review). Cochrane Database Syst Rev 2006; 1: CD003345.
24. Committee on Fluid Resuscitation for Combat Casualties. Fluid Resuscitaiton: state of the
science for treating combat casualties and civilian trauma. Report of the Institute of Medicine.
Washington: National Academy Press; 1999.
25. Sharrock NE, Fischer G, Goss S. The Early Recovery of Cognitive Function After Total-Hip
Replacement Under Hypotensive Epidural Anesthesia. Reg Anesth Pain Med 2005;30:123-127.
26. Williams-Russo P, Sharrock NE, Mattis S. Randomized Trial of Hypotensive Epidural Anesthesia
in Older Adult. Anesthesiology 1999; 91:926–35
27. Sum DC, Chung PC, Chen WC: Deliberate hypotensive anesthesia with labetalol in
reconstructive surgery for scoliosis. Acta Anaesthesiol Sin 1996 Dec;34(4):203-207.
28. Precious DS, Splinter W, Bosco D: Induced hypotensive anesthesia for adolescent orthognathic
surgery patients. J Oral Maxillofac Surg 1996 Jun;54(6):680-683.
29. Nelson CL, Fontenot HJ: Ten strategies to reduce blood loss in orthopedic surgery Am J Surg
1995; 170(6): S64-68.
30. Lu YQ, Cai XJ, Gu LH, et al. Early difference in apoptosis of intestinal mucosa of rates with
severe uncontrolled hemorrhagic shock after three fluid resuscitation methods. Chin Med J 2006;
119(10): 858-63.