Comparison of Permissive Hypotension vs. Conventional Resuscitation Strategies in Adult Trauma Patients with Hemorrhagic Shock: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials.


 BackgroundThere is still an ongoing battle against the Permissive Hypotension (PH) through Conventional Resuscitation Strategies (CR). Active fluid resuscitation in patients with traumatic shock can bring many problems, as it is known that standard high-volume resuscitation can exacerbate the lethal triad of acidemia, hypothermia, and coagulopathy. As a part of damage control resuscitation strategy, it can reduce mortality and shorten hospital stay, compared with the use of standard liquids. Moreover, its application is gradually receiving wider attention (1) . This review evaluated the effectiveness and safety of permissive hypotension resuscitation in adult patients with traumatic hemorrhagic shock.MethodsThe systematic review and meta-analysis were conducted according to PRISMA guidelines. We searched PubMed, EMBASE and Cochrane databases for randomized controlled trials (RCTs) from the beginning to March 2021 to compare the therapeutic effects of controlled fluid resuscitation and conventional fluid resuscitation on patients with traumatic hemorrhagic shock. Two reviewers independently conducted screening, data extraction and bias assessment. Data analysis was performed using Cochrane Collaboration Software Revman 5.2. The primary outcome was 30-day or in-hospital mortality. Secondary outcomes included blood routine index, coagulation function, resuscitation fluid use, complications, and length of hospital stay. Pooling was performed with a random-effects model.Results8 randomized controlled trials were screened out of 898 studies and 1593 patients were evaluated. The target blood pressure of the intervention group ranged from 50-90 mmHg in systolic pressure or mean arterial pressure ≥ 50 mmHg, while that of the control group was 65-110 mmHg systolic pressure or mean arterial pressure ≥ 60 mmHg. Only patients with penetrating injuries were evaluated in two studies, while the remaining six included blunt injuries. A statistically significant reduction in mortality was observed in the intervention group (RR = 0.70; 95%CI= 0.58-0.84; P < 0.05). Small heterogeneity was observed in the included articles (χ2 = 8.9; P = 0.18; I2 = 33%). The loss of platelet (PLT), hemoglobin (Hb) and body fluid was properly protected, the amount of resuscitation fluid was reduced, and the incidence of some adverse events was effectively reduced. There was no significant difference in coagulation time and hospital stay between the two groups.ConclusionsThis meta-analysis reveals the survival benefits of hypotension resuscitation in patients with traumatic hemorrhagic shock. The significant advantage is to promote the recovery of patients' physical function and reduce the incidence of treatment-related complications such as acute respiratory distress syndrome (ARDS), acute kidney injury (AKI) and multiple organ dysfunction syndrome (MODS), which reduces the mortality. Convincing evidences are provided based on these results, but larger, multicenter, randomized trials are needed to confirm the findings.


Introduction
The concept of permissive hypotension was rst proposed by Cannon and his colleagues in the report in 1918 (2) . "Injection of a uid that will increase blood pressure has angers in itself." He pointed out that before achieving de nite hemostasis, the application of crystalloid uid should be limited to keep blood pressure below the normal threshold. Later, Beecher put forward a similar idea in recalling the experience of rescuing the wounded solider in World War II, "elevation of his systemic blood pressure to about 85 mm Hg is all that is, necessary. And when promote internal bleeding is occurring, it is wasteful of time and blood to attempt to get the patient's blood pressure up to normal." (3).
At present, balanced resuscitation has served as an important principle of resuscitation strategy for trauma patients. A growing number of clinicians began to realize that active lens resuscitation can lead to serious clinical complications and hazards, and large amount of uid resuscitation should be avoided (4)(5)(6) . In the early care of trauma patients, the results will be signi cantly improved if permissive hypotension is used in the process of resuscitation treatment (7) . Permissive hypotension below normal mean arterial pressure and resuscitation goals are bene cial for survival, which has been con rmed in a number of animal studies (8-11) . In 1994, Bickell and his colleagues conducted a landmark study to evaluate and con rm their hypothesis that if uid is limited to the nal hemostasis, hypotension patients with trunk penetrating injury will prove to have survival bene ts, which is the rst time in history to demonstrate the potential value of delayed resuscitation in humans (12,13) . Since then, randomized controlled trials on hypotension resuscitation have been carried out, which needs to be updated and analyzed further.
Therefore, the purpose of this review is to identify randomized controlled trials comparing permissive hypotension with conventional resuscitation strategies in adult trauma patients with hemorrhagic injury. The primary outcome was in-hospital or 30-day mortality. Secondary outcomes included blood routine, coagulation function, resuscitation uid use, complications, and length of hospital stay.

Methods
This systematic review and meta-analysis adhere to the reporting guidelines of the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) statement (14).

Study Eligibility Criteria:
Population: We included studies evaluating adult patients with penetrating or blunt trauma and suspected bleeding, and excluded studies on patients with traumatic brain injury, studies on pregnant or underage patients, studies with insu cient mortality data, and studies without ethical approval.
Intervention: Permissive hypotension is considered in the intervention group. Compared with the control group, the intervention group was uid limited.
Permissive hypotension is de ned as limited uid resuscitation to maintain adequate organ perfusion. Systolic blood pressure is about 50-90 mmHg or mean arterial pressure is about 50 mmHg. There are no restrictions on speci c blood pressure targets, type or amount of uid administration.
Control: Conventional resuscitation strategy is considered in the control group, which was de ned as free uid resuscitation. Systolic blood pressure was 65-110 mmHg or mean arterial pressure ≥ 60 mmHg (normal blood pressure). There are no restrictions on speci c blood pressure targets, type or amount of uid administration.
Outcome: The primary outcome was in-hospital or 30-day mortality. Secondary outcomes included blood routine, coagulation function, resuscitation uid use, complications, and length of hospital stay.
Study Design: Eligible randomized controlled trials and quasi randomized trials will be included in the study.

Search Strategy
We searched PubMed, EMBASE and Cochrane databases for articles published before February 25, 2021. The strategy was designed under the guidance of adjudicating senior authors Shuguang Zhu and Zhuangrong Huang. In addition, the additional search was carried out for relevant literature and review articles. And we searched references of identi ed studies closely related to research topics. The medical subject headings (MeSHs) used in our searches included "permissive hypotension" "Wounds and Injuries" and "Shock, Hemorrhagic", without language restriction.

Data Collection
Two authors (Yang Zhang and Yaping Ding) independently examined each article found in the search process, scanned the full text of relevant articles, applied inclusion and exclusion criteria, and extracted and recorded data. Differences related to any aspect of the data extraction process are resolved through discussion with a third reviewer, and the nal decision is made by consensus.

Quality Assessment
The quality of included studies was evaluated using the Cochrane Risk of Bias Tool for randomized controlled studies (15).Disagreements were settled by a third-party reviewer (Liang). Quality metrics assessed include sequence generation, allocation concealment, adequacy of blinding, completeness of outcome data and outcome reporting.

Data Synthesis
All statistical analyses were performed using Review Manager 5.2 software from the Cochrane Collaboration (London, United Kingdom). We extracted the proportions and 95% con dence intervals from each study and pooled them using the random effects model. Statistical heterogeneity and inconsistency were measured by using the Cochran Q test and I 2 , respectively(16). Odds ratios (OR) with 95% con dence intervals (CI) were calculated as summary statistics. The pooled OR was calculated with the Mantel-Haenszel method. Weighted mean differences and 95% CIs were computed for continuous variables, again using a xed-effect method in cases of low statistical inconsistency (I 2 ≤ 50%) and using a random-effect method in cases of moderate or high statistical inconsistency (I 2 > 50%) (17). Results were considered statistically signi cant at P< 0.05.

Search results and study characteristics
We selected 898 articles from the search and nally included 8 randomized controlled trials into the analysis ( Fig. 1) (12,(18)(19)(20)(21)(22)(23)(24) . We didn't come across any quasi-randomized trials. The characteristics of the included studies are described in Table 1. Five studies were conducted in North American civilians who visited major trauma centers, while the other three were conducted in China. Two studies only evaluated patients with penetrating injuries, while the remaining six included penetrating injuries combined with blunt injuries. Two studies only studied preoperative resuscitation, two studies only studied intraoperative resuscitation, and three trials studied patients in two periods. In addition, one trial did not mention surgery related resuscitation strategies. All but one study excluded patients with suspected traumatic brain injury.

Assessment of Reporting Bias
The methodological quality of RCTs was assessed by the Cochrane risk-of-bias tool, which consists of six factors: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data and selective reporting (Fig. 2).

Secondary Outcomes
Blood routine index (PLT and Hb) As shown in Figure 4, three trials (12,21,23) compared the platelet values of PH group or CR group. According to the heterogeneity test, a high degree of heterogeneity was exhibited between studies (χ2 =131.35; P < 0.00001; I 2 = 98%). Thus sensitivity analysis was conducted to eliminate the heterogeneity.

Fluid balance and transfusion requirements
As shown in Figure 6, the overall uid resuscitation and blood transfusion of PH group and CR group were analyzed by subgroup. Heterogeneity test showed that packed red blood cell (PRBC), prehospital crystal, emergency department crystal volume and total inputs were highly heterogeneous, while intra operative crystal (χ2 =0.07; P=0.79; I 2 = 0%) and estimated blood loss (χ2 =0.51; P=0.48; I 2 = 0%) had no heterogeneity. It is indicated by the overall effect that the total amount of uid resuscitation in PH group was lower than that in CR group (MD = -564.21; 95%CI=-833.66 to -244.77; P < 0.001), and the estimated blood loss in PH group was less than that in CR group (MD = -721.53; 95%CI=-1326.19 to -116.87; P < 0.05). There was no signi cant difference in the amount of blood transfusion between the two groups (MD = -144.13; 95%CI=-820.53 to 532.27; P =0.68).

Days of ICU or hospital
As shown in Figure 8, two trials (12,22) involving 651 patients compared days of hospital showed less heterogeneity (χ2 =1.32; P =0.25; I 2 = 24%). With 651 patients included, two trials (12, 22) compared days of intensive care unit (ICU). No heterogeneity was exhibited in the test (χ2 =0.66; P =0.42; I 2 = 0%). Based on the overall effect, it is shown that there was no signi cant difference in hospital stay and ICU treatment time between pH group and CR group during hemorrhagic shock resuscitation (MD = -0.65; 95%CI=-2.14 to 0.84; P =0.39).

Discussion
Hemorrhagic shock poses life-threatening risks for trauma patients. In the history of trauma resuscitation treatment, crystal always serves as the standard of uid resuscitation. The traditional shock resuscitation method, that is, early active uid resuscitation, aims to quickly restore effective blood volume and ensure effective perfusion of organs and tissues. However, the infusion of large cold liquid will lead to dilution coagulopathy (loss of coagulation factor in blood or replacement of dilution by uid without coagulation factor) and hypothermic coagulopathy (hypothermia leads to inhibition of enzyme activity related to platelet and coagulation factor function). At this time, increasing blood ow, perfusion and blood viscosity may contribute to the rupture of blood vessel wall thrombosis, which leads to hypothermia, acidemia and coagulopathy. It will eventually aggravate bleeding and further endangers life. Based on this theory, re ections have been given to the signi cance of limited rehydration. Nowadays, the modern management of these patients witnessed a shift from restoring perfusion to maintaining hemostatic capacity. Restrictive uid resuscitation stands as another option for resuscitation treatment, that is, keeping blood pressure low enough to avoid blood loss and rupture of blood clot, and minimizing the sequelae of hemorrhagic shock, which always maintains the perfusion of nal organs (25)(26)(27).
Determined by hospitalization or 30-day mortality, this meta-analysis demonstrates that tolerable hypotension brings greater bene ts for survival than conventional resuscitation. This conclusion is consistent with the fact that limited uid resuscitation can improve the survival rate of patients with active hemorrhagic shock in a large number of animal experiments. These studies consistently showed that the blood loss decreased and survival time under blood loss control prolonged in animals resuscitated to normal or near normal MAP or cardiac index (8, 10, 28) . However, in terms of human beings, accurate data are de cient to guide the best mean arterial pressure management during the period of permissive hypotension. At present, the practices derived from this concept are more re ected in the operation. The major purpose is to reduce the bleeding in the operation eld, create a good vision and reduce the loss of body uid. In spite of the reduction of blood loss and controlled hypotension bene cial in some cases, it is generally recommended that systolic blood pressure be 80-90 mmHg or MAP be about 50 mmHg (29)(30)(31) for patients without contraindications to antihypertensive therapy. In this study, the blood pressure target of intervention group ranged from systolic blood pressure 50-90 mmHg or mean arterial pressure ≥ 50 mmHg.
The summary of the secondary results shows that the permissive hypotension resuscitation strategy is more effective in preventing the further decline of Hb and PLT indexes, thus improving the tissue oxygen delivery. It also boasts advantages in the balancing uid resuscitation and reducing the amount of uid, and appropriately preventing the body uid loss. Studies showed that before effective control of active bleeding, a large number of uid resuscitation can be observed that mitochondrial function is seriously damaged, and tissue oxygen supply is reduced, leading to acidosis (11) . The analysis results suggest that the decline of Hb and PLT and the degree of uid loss are less affected under the permissive hypotension strategy, which can improve the perfusion and oxygen supply of organs and tissues during shock. It is found that permissive hypotension reduced the total amount of resuscitation uid and is of potential signi cance with respect to resource utilization. At the same time, it comes to our notice that there was no signi cant difference in the changes of coagulation indexes and the probability of coagulation related problems between the two groups. Previous studies found that active uid infusion is associated with dilutive coagulation (32) , thus theoretically uid should also be minimized to resolve these concerns.
The complication occurrence during resuscitation of adult traumatic hemorrhagic shock is also an important factor affecting the patient survival. According to the results of meta-analysis, permissive antihypertensive strategy can reduce the incidence of complications, including AKI, ARDS and MODS, which may bring about higher survival rate of pH group than CR group. Common resuscitation uids, such as large amounts of normal saline and lactate Ringer's solution, were revealed to cause various forms of acidosis. Saline can lead to hyperpigmentation metabolic acidosis, which generated decreased cardiac contractility, lowered down renal perfusion and decreased ionic response. Aggressive uid resuscitation is associated with AKI (33)(34)(35) . In contrast, it is in agreement with the research results of cotton et al that hypovolemic uid resuscitation can effectively eliminate in ammatory factors, improve immune function, maintain the stability of blood components, and reduce the incidence of ARDS and MODS (36-40) . We did not nd any consistent difference in the incidence of complications including anemia, infection, thrombocytopenia and DIC between the two groups. Traumatic brain injury (TBI) is common in trauma population, accounting for about half of all trauma deaths (41) . A large number of literatures pointed out that hypotension resuscitation is controversial in patients with suspected TBI. The most fatal problem of permissive hypotension is that the decrease of cerebral perfusion and oxygenation will aggravate the secondary brain injury and increase the mortality. In addition to its advantages, the active uid resuscitation has potential harms as well, particularly for cerebral perfusion. Higher crystalloid infusion to maintain blood pressure results in increased uid extravasation, microvascular damage, brain edema, and increased intracranial pressure, thereby offsetting any bene t from increased arterial blood pressure (27,42).For the patients with hemorrhagic shock complicated with craniocerebral injury, we should focus on whether there is a threshold to maintain proper cerebral perfusion and give full play to the advantages of hypotension resuscitation. A retrospective study of more than 15000 patients with moderate and severe traumatic brain injury showed that the hypotension threshold of traumatic brain injury should be de ned as SBP < 110 mmHg (43).

Strengths and Limitations
Only randomized studies were included in this review, which represents the highest quality of available evidence. By collecting the latest evidence and combining with the previous meta-analysis of this study, this review provides a strong theoretical basis for the survival bene ts of hypotension resuscitation strategy (13,(44)(45)(46).However, we have to consider some limitations in the comprehensive analysis of these review results. Firstly, the quality of the included randomized trials was uneven due to the lack of systematic bias associated with blinding. Secondly, in addition to Bickell's articles, the scale of included studies is generally small, and there are some heterogeneities in research methods. Such results tend to report a larger range of effects, thus it is urgent to carry out large-scale, multicenter, randomized controlled trials to con rm the conclusions. Most of the studies focused on penetrating injury combined with blunt injury. Whether the conclusions drawn from this meta-analysis are applicable to trauma patients caused by other injury mechanisms is still questionable. In addition, in terms of the arterial pressure, with four studies related to arterial pressure and other studies related to systolic blood pressure, a uni ed data reference was not provided for the evaluation of allowable hypotension threshold. It is noteworthy that this study failed to collect enough data to analyze the duration of permissive hypotension in order to avoid the occurrence of adverse events. The speci c implementation plan of permissive hypotension resuscitation needs to be further explored.

Conclusion
Based on a comprehensive analysis of eight randomized controlled trials, this systematic review compares the overall survival bene ts of permissive hypotension resuscitation and conventional resuscitation strategies for adult patients with traumatic hemorrhagic shock. The current research results show that permissive hypotension resuscitation strategy serves as a better option, as it can reduce the mortality of shock patients, promote the recovery of physical function and reduce the incidence of adverse events, such as AKI, ARDS and MODS. However, there are complex questions to be answered, such as the role of lens in hemostasis and resuscitation, coagulation disorders and treatment caused by trauma, duration of permissible hypotension and speci c implementation plan. All of those need further high-quality and dynamic experiments to clarify.  Figure 2 Risk of Bias Graph-review authors' judgments about each risk of bias item presented.

Figure 3
Forest plot of Permissive Hypotension vs. Conventional Resuscitation Strategies, relative to Mortality.    Forest plot of Permissive Hypotension vs. Conventional Resuscitation Strategies, relative to Complications.