Bickell WH, Wall MJ, Pepe PE, Martin RR, Ginger VF, Allen MK, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med. 1994 Oct 27;331(17):1105–9.
Early, aggressive fluid administration was long considered to be the key to the resuscitation of patients who suffered major hemorrhage following trauma. However, experience from the battlefield suggested that too much fluid in patients with continued bleeding may be associated with adverse outcomes. During World War I, Walter Cannon (Fig. 1), a well-renowned physiologist of the time, collaborated with John Fraser, a senior surgeon at the Harvard Base Hospital, to take care of soldiers injured on the battlefield. From their first-hand experience of hypotensive, wounded soldiers, they noted that intravenous fluids aimed to increase blood pressure might be detrimental. They proposed that hemorrhage may arrest spontaneously as the blood pressure drops to levels too low to dislodge the newly formed clot. In their treatise titled “The preventive treatment of wound shock” published in the Journal of the American Medical Association (JAMA) of 1918, they asserted that “Injection of a fluid that will increase blood pressure carries danger in itself.” They proposed that attempting to raise the blood pressure prior to achieving hemostasis through surgical intervention leads to “loss of blood that is sorely needed” (1).
The experience during World War II echoed these findings. Henry Beecher (Fig. 2), Harvard’s first chief anesthesiologist, served in the US army during the war. He often encountered the harrowing experience of resuscitating wounded soldiers in “shock tents” on the battlefields of Italy and North Africa. From his own experience, he recommended a systolic BP of no more than 80 mm Hg if there was a good pulse and the peripheries were warm. He suggested that blood transfusion may be withheld until definitive surgical intervention is carried out to arrest the bleeding (2).
The Vietnam war blew a wind of change in resuscitation practice. Large-volume resuscitation was often resorted to with the emerging concept of 3:1 volume replacement with crystalloids (3). The recommendations of the Advanced Trauma Life Support (ATLS) guidelines followed, advocating the rapid infusion of 2 L of crystalloid in hemorrhagic shock (4). However, the harmful effects of excessive crystalloid resuscitation were soon evident, with the development of acute respiratory distress syndrome, bowel and myocardial edema, abdominal and extremity compartment syndrome (5). There was also growing concern based on animal models of traumatic hemorrhage, that an aggressive crystalloid resuscitation strategy might lead to clot disruption and increase the risk of hemorrhage, thereby leading to reduced survival (6).
The landmark Bickell et al. paper (1994)
Against this background, Bickell et al. sought to test the hypothesis that in hypotensive patients with penetrating torso injuries, delaying fluid resuscitation until surgical intervention and arrest of bleeding would lead to improved outcomes (7).
Population and design
The study was conducted through the Houston Emergency Medical Services system during a 3-year period between November 1989 to December 1992. Patients 16 years or older who sustained stab or gunshot injury to the torso with a systolic BP of ≤ 90 mm Hg were eligible. The victims were transferred by paramedics to the major trauma center at the Ben Traub General Hospital in Houston, Texas. Patients with fatal gunshot wounds to the head and those with minor injuries that did not require surgical intervention were excluded from the outcome analysis.
Study patients were treated based on an immediate or a delayed resuscitation protocol. The immediate resuscitation strategy was followed on even-numbered and a delayed strategy on odd-numbered calendar days.
Immediate resuscitation group
In the immediate resuscitation group, two or more 14G intravenous cannulae were inserted; fluid resuscitation was commenced with Ringer’s acetate solution before surgical intervention in the pre-hospital and trauma care setting. Patients who arrived at the emergency department with a systolic BP of ≤100 mm Hg continued to receive crystalloid resuscitation. Packed red cells were administered according to the criteria of the American College of Surgeons trauma committee.
Delayed resuscitation group
Intravenous cannulae were inserted in the delayed resuscitation group, but no fluid was administered. Fluids and blood products were administered once the patient was in the operating room and after induction of anesthesia.
Common management in both groups
Endotracheal intubation was carried out, and mechanical ventilation commenced as appropriate, followed by rapid transfer to the trauma center. After arrival to the operating room and induction of anesthesia, crystalloids and packed red cells were administered to both groups to maintain a systolic BP of 100 mm Hg, a hematocrit of ≥25%, and a urine output of at least 50 ml/hour. Hetastarch was occasionally used for intravascular volume expansion.
The sample size was calculated based on expected mortality of 35% in patients with penetrating torso injuries. The authors assumed a 10–15% improvement in survival with a delayed resuscitation strategy. Six hundred patients were required for a two-tailed p-value of 0.05 with 80% power. Analysis was based on intention to treat.
A total of 1069 patients with penetrating torso injuries and hypotension were transferred to the trauma center during the study period. Among these, 172 patients who suffered cardiopulmonary arrest and 299 patients who did not require major surgical intervention were excluded. Of the remaining patients, 309 were assigned to the immediate resuscitation group and 289 to the delayed resuscitation group. The patients were well-matched at baseline; the most common site of injury was the abdomen, followed by chest and neck injuries. The injury severity score (ISS) was 26 ± 14 in both groups. The systolic BP was significantly higher, and the hemoglobin level significantly lower in the immediate resuscitation group upon arrival to the trauma center.
Seventy patients died before they reached the operating room. Among the remaining 528 patients who underwent surgical intervention, 268 were in the immediate resuscitation group and 260 in the delayed resuscitation group. On arrival to the operating room and before the induction of anesthesia, the blood pressures, the venous pH, and bicarbonate levels were similar in both groups.
The volume of fluids administered
The delayed resuscitation group received fluids along with administration of antibiotics, contrast media, and a minimum flow was maintained to ensure venous patency. In the pre-hospital phase, the immediate resuscitation group received a mean volume of 870 ml of fluid compared with 92 ml in the delayed group. At the trauma center, the corresponding volumes administered were 1608 ml and 283 ml. There was no significant difference in the volume of fluid administered intraoperatively between the two groups. Similar volumes of packed red cells, autologous transfusions, fresh frozen plasma, and platelets were administered to both groups.
Survival to hospital discharge, the primary outcome, was significantly higher with the delayed resuscitation strategy. In the immediate resuscitation group, 193/309 (62%) patients survived, compared with 203/289 (70%) in the delayed resuscitation group (p = 0.04). The results remained significant after adjustment for the time interval spent at the scene and at the hospital prior to arrival in the operating room. Intraoperative blood loss was similar in both groups, although there was a non-significant increase in the immediate resuscitation group. The duration of ICU stay was similar between the two groups; however, the duration of hospital stay was significantly longer in the immediate resuscitation group.
The beneficial effect of a delayed resuscitation strategy seemed more pronounced among patients with more severe injury. The survival rate in patients with an Injury Severity Scores of ≥25 or higher was 61% in the delayed resuscitation group compared with 48% in the immediate resuscitation group (P = 0.02).
Based on these findings, the authors proposed that fluid resuscitation should be delayed in hypotensive patients with penetrating torso injuries until they were ready for operative intervention aimed at achieving hemostasis. The lower hemoglobin level in the immediate resuscitation group could likely have been due to continued bleeding; besides, excessive fluid administration may also have resulted in the coagulopathy observed in this group. The authors suggested that their study did not support the practice of aggressive fluid resuscitation for all patients with trauma and hypotension, presumably related to hemorrhage. They contended that although the necessity of fluid resuscitation remained unquestioned, the timing and the volume need to be reconsidered in light of their findings. They recommended future studies to explore the concept of delayed resuscitation in blunt trauma.
The Bickell et al. study was among the first controlled trials that evaluated the concept of hypotensive resuscitation in bleeding trauma patients. The study was adequately powered to estimate a survival benefit with the delayed resuscitation strategy. Analysis was based on intention to treat. The study confirmed a physiologically plausible hypothesis that excessive fluid administration in the face of continued bleeding could lead to harm emanating from potential clot dislodgement and coagulopathy.
Patients were assigned to the study group using a quasi-randomized, alternate-day method. According to the authors, this design was chosen to avoid delays in resuscitation that may have occurred with conventional methods of randomization. Questions were raised about Ringer’s acetate, the resuscitation fluid used by the investigators, that could potentially cause hypotension due to the release of adenosine and vasodilatation. The volume of fluid administered in the immediate resuscitation group was lower than expected, with a mean volume of 133 ml of packed red cells and 1.6 L of crystalloid. In the delayed resuscitation group, 22 patients received early resuscitation fluid, which could have affected outcomes. The single-center study was conducted in an established trauma system; patients were ready in the operating room within an average duration of 79 minutes of the trauma call. Surgical intervention was carried out expeditiously, within 40–50 minutes of arrival at the trauma center. Similar timelines may be difficult to achieve in other healthcare settings. Hence, these results may not be generalizable to less experienced trauma systems.
Later studies that explored the concept of limited resuscitation
The Bickell et al. study triggered considerable research and many controlled trials to further explore the concept of limited early resuscitation of trauma victims.
Following this landmark trial, the Fluid Resuscitation in Trauma (FRT) study was undertaken between 1996–1999 (8). The FRT study included patients with blunt or penetrating injury who were actively bleeding with a systolic BP of less than 90 mm Hg recorded within an hour of injury. Unlike the Bickell et al. study, patients were randomized to receive resuscitation fluids titrated to a systolic BP of >100 mm Hg or 70 mm Hg. Once the target BP was achieved, a policy of fluid restriction was followed, with the appropriate use of sedative or analgesic drugs aimed to maintain blood pressure within the target range. The resuscitation strategy was continued until hemostasis was achieved. The study included 110 patients, with 55 in each group; mortality was low, with four deaths in each group. Although the target of 70 mm Hg was aimed for in the low BP arm, the mean systolic BP was 100 mm Hg compared with 114 mm Hg in the high BP group. The authors concluded that a strategy aimed at deliberate hypotension did not lead to higher mortality in the trauma patient with active bleeding.
A later pilot study by Schreiber et al. evaluated the safety and feasibility of a controlled compared with a standard resuscitation strategy in hypotensive trauma patients (9). Patients included in this study had a systolic BP ≤90 mm Hg. In the controlled resuscitation group, a 250 ml bolus fluid was administered if there was no palpable radial pulse or if the systolic BP was <70 mm Hg. Additional boluses of 250 ml were administered to maintain the systolic BP ≥70 mm Hg. In the standard resuscitation group, an initial bolus of 2 L of fluid was administered, followed by additional boluses to maintain the systolic BP ≥110 mm Hg. The protocol was followed until hemostasis was achieved or until 2 hours after arrival at the hospital. The mean volume of intravenous fluid administered was 1 L in the controlled resuscitation group compared with 2 L in the standard group. At 24 hours post-admission, a trend towards lower mortality was observed in the controlled resuscitation group, although the difference was not statistically significant (5% vs. 15%). In blunt trauma victims, the 24-hour survival was significantly higher with a controlled compared with a standard resuscitation strategy (3% vs. 18%). The authors suggested that a controlled resuscitation strategy may improve early survival in trauma patients with ongoing hemorrhage.
In contrast to the above studies, Carrick et al. did not observe a 30-day survival advantage with a hypotensive strategy among patients who underwent thoracotomy or laparotomy for hemorrhage control. In this study, a target mean arterial pressure (MAP) target of 50 mm Hg was compared with a higher MAP of 65 mm Hg (10).
Conventional resuscitation practice in severe trauma was based on the administration of large volumes of intravenous fluid with the aim of restoring hemodynamic stability and preserving organ function. This dictum was largely based on animal studies from the 1950s that suggested improved outcomes in traumatic hemorrhage with the normalization of hemodynamic parameters. However, in the clinical setting, there was increasing concern that attempts to restore intravascular volume before hemorrhage control was attained could lead to deleterious effects arising from clot dislodgement and continued bleeding. Besides, excessive administration of intravenous fluids in the bleeding patient could lead to dilutional coagulopathy and reduce blood viscosity, contributing to secondary hemorrhage. These mechanisms could entail reduced survival in patients who were subjected to overzealous fluid resuscitation. The Bickell et al. study challenged conventional wisdom and contemporaneous guidelines of the era that recommended large-volume fluid resuscitation among all hypotensive trauma patients, irrespective of the attainment of hemorrhage control. Although the study had several limitations, including a suboptimal, quasi-randomized design, it led to a rethink among clinicians regarding the appropriateness of aggressive resuscitation measures in the bleeding trauma patient. Over the years, permissive hypotension came to be incorporated as a basic tenet of “damage control” resuscitation along with control of life-threatening hemorrhage and prevention of contamination arising from visceral injury (11). Continued resuscitation with definitive measures to correct physiologic derangements follows the initial phase of damage control. This paper underlined the importance of avoiding an aggressive fluid resuscitation strategy in hypotensive patients following penetrating torso trauma. The overriding emphasis lies in the control of hemorrhage through timely surgical intervention. A harbinger of change, this landmark trial reasserted the “less is more” concept in critical care practice.
1. WB Cannon: a trauma pioneer – ST Horne, 2004 [Internet]. [cited 2023 Jan 31]. Available from: https://journals.sagepub.com/doi/abs/10.1191/1460408604ta301oa
2. Beecher HK. Preparation of Battle Casualties for Surgery. Ann Surg. 1945 Jun;121(6):769–92.
3. Shires GT, Canizaro PC. Fluid resuscitation in the severely injured. Surg Clin North Am. 1973 Dec;53(6):1341–66.
4. Bell RM, Krantz BE, Weigelt JA. ATLS: a foundation for trauma training. Ann Emerg Med. 1999 Aug;34(2):233–7.
5. Maxwell RA, Fabian TC, Croce MA, Davis KA. Secondary abdominal compartment syndrome: an underappreciated manifestation of severe hemorrhagic shock. J Trauma. 1999 Dec;47(6):995–9.
6. 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 Feb;22(2):155–63.
7. Bickell WH, Wall MJ, Pepe PE, Martin RR, Ginger VF, Allen MK, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med. 1994 Oct 27;331(17):1105–9.
8. Dutton RP, Mackenzie CF, Scalea TM. Hypotensive resuscitation during active hemorrhage: impact on in-hospital mortality. J Trauma. 2002 Jun;52(6):1141–6.
9. Schreiber MA, Meier EN, Tisherman SA, Kerby JD, Newgard CD, Brasel K, et al. A controlled resuscitation strategy is feasible and safe in hypotensive trauma patients: results of a prospective randomized pilot trial. J Trauma Acute Care Surg. 2015 Apr;78(4):687–95; discussion 695-697.
10. Carrick MM, Morrison CA, Tapia NM, Leonard J, Suliburk JW, Norman MA, et al. Intraoperative hypotensive resuscitation for patients undergoing laparotomy or thoracotomy for trauma: Early termination of a randomized prospective clinical trial. J Trauma Acute Care Surg. 2016 Jun;80(6):886–96.
11. Shapiro MB, Jenkins DH, Schwab CW, Rotondo MF. Damage control: collective review. J Trauma. 2000 Nov;49(5):969–78.
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