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Three Part Question

In [patients with solid organ injury following blunt abdominal trauma] is [chemical thromboprophylaxis] a [safe early intervention in non-operative clinical management]

Clinical Scenario

A 45 year old man (Mr X) sustained significant trauma in a road traffic accident (RTA). From clinical examination and a trauma series CT scan Mr X is diagnosed with grade 3 liver and splenic injuries. Mr X is haemodynamically stable and has no evidence of ongoing bleeding, initial plan is to manage the patient non-operatively. Mr X is in significant discomfort and is not mobilising from bed, you wonder about the safety of prescribing low molecular weight heparin (LMWH) venous thromboembolism (VTE) prophylaxis.

Search Strategy

We searched the databases Medline (1946 - September 2017), Embase (1974 - September 2017) and Cinahl (1981 - September 2017) via NHS NICE HDAS interface.
We also searched the Cochrane Central Register of Controlled Trials (September 2017) & Cochrane Database of Systematic Reviews (September 2017)




Using search terms:

(thrombus* OR thrombotic* OR thrombolic* OR thromboemboli* OR thrombos* OR thromboph* OR deep* OR vein* or ven* OR thromb* or embol* OR pulmonary OR lung* OR thromb* OR embol* OR DVT or PE or VTE)
AND (solid organ injury OR organ injury OR blunt abdominal trauma OR abdominal injury OR Abdominal trauma OR blunt trauma OR abdominal organ injury OR splenic injury OR liver injury OR kidney injury OR splenic trauma OR liver trauma OR kidney trauma)
AND (thromboprophylaxis OR prophylactic* OR prophylaxis)

Search Outcome

Our search identified 910 papers. After reviewing title and abstract of 910 papers, 902 papers were excluded to only include original studies assessing the safety of pharmacological thrombo-prophylaxis in patients with blunt trauma solid organ injuries receiving non-operative management (NOM).

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Norwood S, et al 2001 USA	This study included 22 patients sustaining solid organ injuries (SOI) from blunt trauma who underwent non-operative management (NOM) and received LMWH prophylaxis in <24 hours. liver injuries n=10, and splenic injuries n=12	Prospective cohort study	Failure of non-operative management (NOM)	No patient with liver injury failed NOM, however, two of the 12 patients with splenic injuries failed NOM. The two patients who failed NOM had a high grade injury.	Small sample of patients with abdominal solid organ injury (SOI). This study did not include a control group for comparison.
Alejandro K, et al 2003 Puerto Rico	This study included 114 patients over 18 years old sustaining blunt trauma splenic injuries, underwent NOM and received LMWH prophylaxis; Early LMWH (<48 hours) n=50 or Late LMWH (>48 hours) n=64	Retrospective cohort study, level 3	Failure of NOM	There was no statistical difference in failure of NOM between early or late LMWH groups p= 0.593	The study has a relatively small sample size. The late LMWH group included patients who did not receive LMWH . Although it was not statistically significant, a higher proportion of patients in the late LMWH group had moderate-severe splenic injuries. This study only included patients with splenic injury.
				The failure rate of NOM is low. Only 4% of patients in early group and 6% in the late LMWH group failed NOM.
			Blood transfusion requirement	Requirement of blood transfusions were similar p=0.507
Eberle BM, et al, 2011 USA	This study included 312 patients over 15 years old, who sustained blunt trauma, liver, kidney or splenic injuries, underwent NOM and received LMWH prophylaxis; Early LMWH <3 days n=41 (13.2%), Late KMWH >3 days n=70 (22.4%) or No LMWH n=201 (64.4%)	Retrospective cohort study, level 3	Failure of NOM	Overall (5.4%) failed NOM (7.8% spleen, 2.1% liver, and 3.1% kidney)	Significant differences exist between comparison groups. The late LMWH group patients had a higher average injury severity score. Pelvic and lower extremity fracture were significantly more common in the early and late LMWH groups compared to the group not receiving LMWH p=0.001. The study did not use routine screening to aid diagnosis of thromboembolic disease.
				There was no significant difference of NOM failure between the early, late or no LMWH groups
			Blood transfusion requirements	Greater requirement of blood transfusion in the late LMWH compared to early LMWH group. (Early group - 3.0 ± 5.3 units vs Late group - 6.4 ± 9.9 units; p = 0.027)
			Incidence of DVT or PE, diagnosed clinically (not through routine screening)	There were four cases of venous thromboembolic (VTE) disease. The overall incidence of VTE was 1.3% and all occurred before the administration of LMWH. VTE disease was diagnosed clinically and not through routine screening.
Joseph B, et al 2015 USA	This study included 145 patients with blunt trauma SOI (liver, kidney, spleen) underwent NOM and received LMWH prophylaxis; Early LMWH <48 hours n=58, Intermediate LMWH 48 to 78 hours n=29 or Late LMWH >72 hours n=29	Retrospective cohort study, level 3	Failure of NOM	No patient failed NOM	Relatively small sample size
			Requirement of angio-embolisation	One patient in each group required angio-embolisation, all of these patients had high grade splenic injuries
			Blood transfusion requirement	No significant difference of blood transfusion requirements
			Incidence of VTE	Two patients with high grade injuries developed DVT, one in the intermediate and one in the late group
Rostas J, et al 2015 USA	This study included 328 patients with blunt trauma liver and splenic injuries who underwent NOM and received LMWH prophylaxis; Early LMWH <48 hours n=103 (31%), Intermediate LMWH 48 - 72 hours n=54 (17%) or Late LMWH >72 hours n= 171 (52%)	Retrospective cohort study, level 3	Failure of NOM	No patients failed NOM after administration of LMWH	There were differences between comparison groups. There were fewer high grade liver and splenic injuries in the early LMWH group. The late LMWH group had a significantly higher average injury severity score.
			Blood transfusion requirement	No difference in blood transfusion requirement
			Incidence of VTE (diagnosed clinically, not through routine screening)	One patient (0.6%) in the early group, no patients in the intermediate group and six patients (2.8%) in the late group were diagnosed with VTE disease
Murphy P, et al 2015 Canada	This study included 162 patients over 18 years old sustaining blunt trauma splenic injuries, underwent NOM and received LMWH prophylaxis; Early LMWH (<48 hours) n=78 or Late LMWH(>48 hours) n=84	Retrospective cohort study, level 3	Failure of NOM	No statistically significant difference in NOM failure.	Differences existed between comparison groups. Significantly more high grade splenic injuries were in the delayed (late) LMWH group. The late LMWH group included patients who did not receive LMWH. This study only included patients with splenic injury. No screening was used to diagnose VTE.
			Blood transfusion requirement	No difference blood transfusion requirement
			Incidence of VTE (diagnosed clinically, not through routine screening)	Two cases of PE and one DVT in the early prophylaxis group
kwok A, et al 2016 USA	This large study included 474 patients over 13 years old sustaining blunt trauma splenic injuries, underwent NOM and received VTE prophylaxis (enoxaparin, or heparin if concurrent renal impairment); Immediate <24 hours n=23, Early (24-48 hours) n=91, Intermediate (48-72 hours) n=65, Late >72 hours n= 77 or patients who did not receive LMWH n=241	Retrospective cohort study, level 3	Failure of NOM	VTE prophylaxis did not affect failure rate of NOM compared to the group who did not receive prophylaxis p=0.39	Significant differences existed between the comparison groups. Despite the group not receiving VTE prophylaxis having a greater number of grade IV splenic injury, this group had a lower average injury severity score. Patients with high grade splenic injuries that received LMWH were more often prescribed delayed VTE prophylaxis. This study only included patients with splenic injury.
				No significant difference in failure of NOM between groups of patients who receive LMWH immediately, early, intermediate or late p=0.95
			Blood transfusion requirement	No significant difference in blood transfusion requirements
Khatsilouskaya T, et al 2017 Switzerland	179 Adult trauma patients with solid organ injury (SOI) (liver, spleen, kidney) underwent NOM and received LMWH or unfractionated heparin ; Early <72 hours n=80 , Late >72 hours n=62, or None given n=37	Retrospective cohort study, level 3	Failure of NOM	The overall failure rate of NOM was 3.9%	There were differences between comparison groups. The injury severity score (ISS) was significantly higher in the late prophylaxis group. Significantly more patients with pelvic and lower limb fracture received anticoagulation compared to the no heparin group p=0.012. Significantly more high grade SOI in the no heparin group. VTE was diagnosed clinically, not through the use of routine screening.
				NOM failure of patients with splenic injuries occurred more often in the no VTE prophylaxis group compared to the late or early prophylaxis groups (10.8, 4.8 and 1.3% respectively) p=0.043
			Incidence of VTE (diagnosed clinically, not through routine screening)	No statistically significant difference of VTE incidence, however, more often VTE was diagnosed in patients from the late and no heparin group.

Comment(s)

Non-operative management (NOM) of blunt trauma solid organ injury (SOI) in haemodynamically stable patients has become standard practice of care (9,10). Venous thromboembolism (VTE) is a life threatening complication of major trauma (11). Prothrombotic changes in physiology are hypothesised to occur within 48 hours following trauma (12). Chemical VTE prophylaxis is superior to mechanical VTE prophylaxis (13). Mechanical prophylaxis may be precluded in blunt trauma if there is associated lower limb injury. The American College of Chest Physicians and Eastern Association for the Surgery of Trauma clinical guidelines suggest early administration of chemical VTE prophylaxis (14,15), but do not specify its timing, and there is a lack of evidence to inform of its safety in early NOM of blunt trauma SOI. 
Most current evidence assessing the safety of early chemical thrombo-prophylaxis (low molecular weight heparin or unfractionated heparin) are retrospective cohort studies. Retrospective cohort studies are vulnerable to selection bias as patients enter respective treatment arms based on the preference of the treating physician. In many of the studies included in this analysis, significant differences existed between the comparison groups. Discrepancies in these groups likely reflect the treating physicians reluctance to initiate low molecular weight heparin (LMWH) in patients identified to have a high grade SOI or patients with a higher average injury severity score. Many of the studies available have relatively small sample sizes to detect differences in failure of NOM. Eberle et al reported failure of NOM for patients not receiving thrombo-prophylaxis of 7% (4), which means to detect a difference of 10% in failure rates with 80% power a study requires a sample size of 165 patients in each respective comparison group. Only two studies investigated administration of LMWH within 24 hours, Norwood et al in a prospective study which did not include a comparison group and Kwok et al who did not find that administration of LMWH within 24 hours increased failure rate of NOM or requirement of blood products. There are differences between the studies in patient population, chemical prophylaxis regimens, and the classification of early and late administration. Most studies used LMWH and defined early administration of LMWH as occurring within 48 hours. These studies show that administering LMWH within 48 hours does not increase failure rate of NOM or the increase the requirement for blood products. These studies suggest that administration of LMWH within 48 hours is safe in patients who sustain SOI from blunt trauma being receiving NOM. 


Editor Comment

KMJ

Clinical Bottom Line

There is inadequate evidence assessing safety of LMWH within 24 hours of trauma.
 The current available evidence of retrospective studies do suggest that administration of LMWH within 48 hours is safe in early NOM of patients who have sustained SOI from blunt trauma. However, a large multi centre randomised prospective study is warranted to investigate further before confidently concluding the safety of early chemical thomboprophylaxis in early NOM of SOI.

References

1. Norwood SH, McAuley CE, Berne JD, Vallina VL, Kerns DB, Grahm TW, McLarty JW A potentially expanded role for enoxaparin in preventing venous thromboembolism in high risk blunt trauma patients American College of Surgeons (J Am Coll Surg) (2001); 192: 161-167
2. Alejandro KV, Acosta JA, Rodriguez PA Bleeding manifestations after early use of low-molecular-weight heparins in blunt splenic injuries The American Surgeon (Am Surg) (2003); 69: 1006 –1009
3. Eberle BM, Schnu ̈riger B, Inaba K, et al. Thromboembolic prophylaxis with low-molecular-weight heparin in patients with blunt solid abdominal organ injuries undergoing non-operative management: current practice and outcomes The Journal of Trauma: Injury, Infection, and Critical Care (J Trauma) (2011); 70: 141–147
4. Joseph B, Pandit V, Harrison C, Lubin D, Kulvatunyou N, Zangbar B, et a Early thromboembolic prophylaxis in patients with blunt solid abdominal organ injuries undergoing nonoperative management: is it safe? American Journal of Surgery (Am J Surg) (2015); 209: 194–198
5. Rostas JW, Manley J, Gonzalez RP, Brevard SB, Ahmed N, Frotan MA, et al The safety of low molecular-weight heparin after blunt liver and spleen injuries American Journal of Surgery (Am J Surg) (2015); 210: 31–34
6. Murphy PB, Sothilingam N, Stewart TC, Batey B, Moffat B, Gray D, et al Very early initiation of chemical & venous thromboembolism prophylaxis after blunt solid organ injury is safe Canadian Journal of Surgery (Can J Surg) (2016); 59: 118–122

7. Kwok A, Davis J, Dirks R, Wolfe M, Kaups K Time is now: venous thromboembolism prophylaxis in blunt splenic injury American Journal of Surgery (Am J Surg) (2016); 212: 1231-1236
8. Khatsilouskaya T, Haltmeier T, Cathomas M, Erberle B, Candinas D, Schnuriger B. Thromboembolic Prophylaxis with Heparin in Patients with Blunt Solid Organ Injuries Undergoing Non-operative Treatment World Journal of Surgery (World J Surg) (2017); 41: 1193-1200
9. Stassen NA, Bhullar I, Cheng JD et al Nonoperative management of blunt hepatic injury: an Eastern Association for the Surgery of Trauma practice management guideline Trauma Acute Care Surg (2012); 73: 288–293 

10. Zarazur BL, Kozar R, Myers JG, et al The splenic injury outcomes trial: an American Association for the Surgery of Trauma multi- institutional study J Trauma Acute Care Surg (2015); 79: 335–342
11. Geerts WH, Code KI, Jay RM, et al A prospective study of venous thromboembolism after major trauma N Engl J Med (1994); 331:1601–1606
12. Chapman BC, Moore EE, Barnett C, et al Hypercoagulability following blunt solid abdominal organ injury: when to initiate anticoagulation Am J Surg (2013); 206: 917–922
13. Barrera LM, Perel P, Ker K, Cirocchi R, Farinella E, Morales Uribe CH Thromboprophylaxis for trauma patients Cochrane Database Syst Rev (2013); (3): CD008303 

14. Kearon C, Akl EA, Comerota AJ, et al Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest (2012); 141: e419S–94S
15. Rogers FB, Cipolle MD, Velmahos G, et al Practice management guidelines for the prevention of venous thromboembolism in trauma patients: the EAST practice management guidelines work group J Trauma Acute Care Surg (2002); 53: 142-164