Ivermectin for Prevention and Treatment of COVID-19 Infection

          Ivermectin for Prevention and Treatment of COVID-19 Infection

                                                 Dr. KS Dhillon

Ivermectin oral tablet is used to treat infections of parasites. These include parasitic infections of our intestinal tract, skin, and eyes. It is also available as a topical cream and topical lotion. Ivermectin oral tablet is available as the brand-name drug Stromectol. 

Ivermectin tablet works by binding to parts inside the parasite. It eventually paralyzes and kills off the parasite, and it also stops adult parasites from making larvae for some time. This results in the eradication of the parasitic infection. 

In recent years several groups have shown, in-vitro, that ivermectin has anti-viral activity against a broad range of viruses [1]. Due to its in vitro antiviral activity against a broad range of viruses, it has been used off-label for the treatment of some viral diseases. 

Several studies have reported antiviral effects of ivermectin on RNA viruses such as dengue, Zika, yellow fever, West Nile, Hendra, Newcastle, Venezuelan equine encephalitis, chikungunya, Semliki Forest, Sindbis, Avian influenza A, Porcine Reproductive and Respiratory Syndrome, Human immunodeficiency virus type 1, and severe acute respiratory syndrome coronavirus 2. There are also some studies that show antiviral effects of ivermectin against DNA viruses such as Equine herpes type 1, BK polyomavirus, pseudorabies, porcine circovirus 2, and bovine herpesvirus 1.

Ivermectin has been found to have antiviral action against the SARS-CoV-2 clinical isolate in vitro. A single dose of ivermectin is able to control viral replication within 24–48 hours by inhibiting IMPα/β1-mediated nuclear import of viral proteins [1].

Ivermectin has an established safety profile for human use [2,3,4] and is FDA-approved for several parasitic infections [2,4]. Recent reviews and meta-analyses indicate that high-dose ivermectin has comparable safety as the standard low-dose treatment [5]. There, however, is not enough evidence to make conclusions about the safety profile in pregnancy.

Many drugs with anti-inflammatory, antiviral, and immunomodulatory properties are currently used in the treatment of COVID-19. Unfortunately, none of them can provide a complete cure [6]. One of the drugs whose effectiveness has been and is being investigated in the treatment of  COVID-19 is ivermectin.

Up to February 2021, the Pan American Health Organization (PAHO) identified twenty-two ivermectin randomized clinical trials through a rapid review of current available literature [7]. In these studies, there is considerable heterogeneity in the population receiving ivermectin, with studies administering it to family contacts of confirmed COVID-19 cases as a prophylactic measure [8], other studies using ivermectin for treatment of mild and moderate disease [9], and even in patients who are hospitalized with severe disease [10]. 

Kim et al [11] recently published a systematic review and network meta-analysis that compared the efficacy and safety of pharmacological interventions for COVID-19 in hospitalized patients. The review included 110 studies (78 published and 38 unpublished) with 40 randomized clinical trials and 70 observational studies. Based on the observational data, they found that high-dose intravenous immunoglobulin, tocilizumab, and ivermectin were associated with a reduced mortality rate in critically ill patients. They also found that none of the analyzed drugs were significantly associated with increased non-cardiac serious adverse events compared to standard care.

Kow et al [12] carried out a meta-analysis to study the association between the use of ivermectin and mortality in patients with COVID-19. The study included 6 randomized controlled trials with a total of 658 patients who were randomized to receive ivermectin and 597 patients randomized in the control group who did not receive ivermectin. The meta-analysis showed significantly reduced odds of mortality with the use of ivermectin among patients with COVID-19 relative to non-use of ivermectin. The estimated effect of ivermectin indicated mortality benefits.

Rajter et al [13] carried out a study that showed that the use of Ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease. Their study included 280 patients, 173 treated were treated with ivermectin and 107 without ivermectin. Most patients in both groups also received hydroxychloroquine, azithromycin, or both. Univariate analysis showed lower mortality in the ivermectin group. Mortality also was lower among ivermectin-treated patients with severe pulmonary involvement. No significant differences were found in extubation rates or length of stay. After multivariate adjustment for confounders and mortality risks, the mortality difference remained significant. Mortality was significantly lower in the ivermectin group. 

Okumus et al [14] carried out a study to evaluate the effectiveness and safety of adding ivermectin to treatment in patients with severe COVID-19.

It was a prospective, randomized, controlled, single-blind phase 3 multicenter clinical trial to assess the effectiveness and safety of ivermectin use in the treatment of patients without mutation. All patients in the study had severe COVID19 pneumonia. Ivermectin 200 mcg/kg/day for 5 days in the form of a solution prepared for enteral use was given to the study group in addition to the reference treatment protocol of hydroxychloroquine, favipiravir, and azithromycin. Patients in the control group were given only reference treatment with 3 other drugs without ivermectin. The study showed that ivermectin provided an increase in clinical recovery, improvement in prognostic laboratory parameters, and a decrease in mortality rates even when used in patients with severe COVID-19. The authors were of the opinion that ivermectin should be considered as an alternative drug that can be used in the treatment of COVID-19 disease or as an additional option to existing protocols.

Shoumann et al [15] carried out a randomized clinical trial to study the use of ivermectin for chemoprophylaxis for covid-19 infection. This was a  prospective interventional randomized open label-controlled study. Two arms were designed according to the use of ivermectin. In the ivermectin arm, contacts of a patient with covid infection received ivermectin on the day of the diagnosis of their index case. The nonintervention group received no ivermectin. Both groups were followed up for two weeks to look for symptoms suggestive of COVID-19.

In the Ivermectin group, there were 203 contacts (to 52 index cases). In the nonintervention group, there were 101 contacts (to 24 index cases). Fifteen contacts (7.4%) developed COVID-19 in the ivermectin arm as compared to 59 (58.4%) in the nonintervention arm. The authors concluded that Ivermectin is suggested to be a promising, effective, and safe chemoprophylactic drug in the management of COVID-19.

Bryant et al [16] carried out a systematic review and meta-analysis to assess the efficacy of ivermectin treatment and/or prophylaxis among people with, or at high risk of covid-19 infection. They searched bibliographic databases up to February 2021. Their study included 21 RCTs involving 2741 participants. Meta-analysis of 13 trials found that ivermectin reduced the risk of death compared with no ivermectin. The evidence was of low to moderate certainty. Low-certainty evidence found that ivermectin prophylaxis reduced covid-19 infection by an average of 86%.

The systematic review and meta-analysis were done using rigorous Cochrane methods. Evidence was assessed using the GRADE approach which judges the certainty of the evidence.

The authors concluded that the apparent safety and low cost of the drug suggest that ivermectin could have an impact on the SARS-CoV-2 pandemic globally. Ivermectin is not a new and experimental drug with safety concerns; it is a WHO ‘essential medicine’ usually used for the treatment of other diseases.

López-Medina et al [17] carried out a randomized clinical trial to determine whether ivermectin is efficacious in the treatment for mild COVID-19. In this double-blind, randomized trial a total of 476 adult patients with mild disease and symptoms for 7 days or fewer (at home or hospitalized) were enrolled

between July 15 and November 30, 2020, and followed up through December 21, 2020. The patients were randomized to receive ivermectin, 300 μg/kg of body weight per day for 5 days (n = 200) or placebo (n = 200).

The median time to resolution of symptoms was 10 days in the ivermectin group compared with 12 days in the placebo group. By day 21, 82% in the ivermectin group and 79% in the placebo group had resolved symptoms. The authors concluded that among adults with mild COVID-19, a 5-day course of ivermectin, compared with placebo, did not significantly improve the time to resolution of symptoms. They said that their findings do not support the use of ivermectin for the treatment of mild COVID-19.

Despite the presence of several randomized clinical trials which show the effectiveness of Ivermectin in the treatment and prophylaxis of covid-19, WHO in its latest 2021 guidelines does not recommend the use of ivermectin for the treatment of covid-19 infections. According to WHO the current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive. WHO recommends that the drug only be used within clinical trials. The WHO panel did not look at the use of ivermectin to prevent COVID-19. 

WHO strongly recommends the use of systemic corticosteroids for severe or critically ill COVID-19 patients. WHO does not recommend the use of remdesivir, hydroxychloroquine, and lopinavir/ritonavir for treatment of covid-19.  WHO provides conditional recommendation for the use of low-dose anticoagulants in hospitalized covid-19 patients. 

The WHO decision was based on the following factors. Their panel found that for most key outcomes, including mortality, mechanical ventilation, hospital admission, duration of hospitalization, and viral clearance, the evidence was of very low certainty. The evidence was rated as very low certainty mainly because of very serious imprecision for most outcomes: the aggregate data had wide confidence intervals and/or very few events. There were also concerns related to the risk of bias for some outcomes, specifically lack of blinding, lack of trial pre-registration, and lack of outcome reporting for one trial that did not report mechanical ventilation despite pre-specifying it in their protocol (publication bias) [18].

There has been some criticism of the WHO analysis [19]. According to the critics, the WHO analysis contains many flaws [19]: 

• Of the 58 studies (29 RCTs) available in the literature, WHO only included 16 in their analysis.
• They excluded all 14 prophylaxis studies (4 RCTs).
• There was no protocol for data exclusion.
• Trials included in the original UNITAID search protocol were excluded.
• They excluded all epidemiological evidence, although WHO has considered such evidence in the past.
• They combine early treatment and late treatment studies and do not provide heterogeneity information. Early treatment is more successful, so pooling late treatment studies will obscure the effectiveness of early treatment. They chose not to do subgroup analysis by disease severity across trials, although treatment delay is clearly a critical factor in COVID-19 treatment, the analysis is easily done, and it is well known that the studies for ivermectin and many other treatments clearly show greater effectiveness for early treatment.
• WHO downgraded the quality of trials compared to the UNITAID systematic review team and a separate international expert guideline group that has long worked with the WHO.
• They disregarded their own guidelines that stipulate quality assessments should be upgraded when there is evidence of a large magnitude effect (which there is), and when there is evidence of a dose-response relationship (which there is). They claim there is no dose-response relationship, while the UNITAID systematic review team found a clear relationship.
• Their risk of bias assessments does not match the actual risk of bias in studies. There is a clear treatment delay-response relationship and very late stage treatment is not expected to be as effective as early treatment. Much higher quality studies were classified as high risk of bias.
• Although WHO's analysis is called a "living guideline", it is rarely updated and very out of date. As of May 14, 2021, four of the missing RCTs are known to WHO and labeled "RCTs pending data extraction" [COVID-NMA]. 
• A single person served as Methods Chair, member of the Guidance Support Collaboration Committee, and member of the Living Systematic Review/NMA team.
• Public statements from people involved in the WHO analysis suggest substantial bias. For example, a co-chair reportedly said that "the data available was sparse and likely based on chance". The data is comprehensive, and we estimate the probability that an ineffective treatment generated results as positive as observed to be 1 in 9 trillion (p = 0.00000000000011). The clinical team lead refers to their analysis of ivermectin as "fighting this overuse of unproven therapies ... without evidence of efficacy", despite the extensive evidence of efficacy from the 58 studies by 519 scientists with 18,776 patients. People involved may be more favorable to the late-stage treatment of COVID-19, for example, the co-chair recommended treating severe COVID-19 with remdesivir.

It is not true that there is no evidence for the use of ivermectin in the prevention and treatment of covid-19 infections. There is evidence but the evidence is apparently weak.

In conclusion, research related to ivermectin use in COVID-19 has several limitations but the evidence continues to grow [20,21]. The use of ivermectin for prophylaxis or treatment for COVID-19 should be done based on trustable evidence, without conflicts of interest, with proven safety and efficacy in patient-consented, ethically approved, randomized clinical trials [22]. There remains a need for large randomized clinical trials to prove the efficacy of ivermectin in the prevention and treatment of covid-19 infections.

Reference

1. Leon Calya, Julian D.Druce, Mike G.Catton, David A.Jans, Kylie M.Wagstaff. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Research. Volume 178, June 2020, 104787.
2. A. Gonzalez Canga, et al. The pharmacokinetics and interactions of ivermectin in humans--a mini-review AAPS J., 10 (1) (2008), pp. 42-46.
3. D.A. Jans, A.J. Martin, K.M. Wagstaff. Inhibitors of nuclear transport Curr. Opin. Cell Biol., 58 (2019), pp. 50-60.
4. D. Buonfrate, et al. Multiple-dose versus single-dose ivermectin for Strongyloides stercoralis infection (Strong Treat 1 to 4): a multicentre, open-label, phase 3, randomised controlled superiority trial Lancet Infect. Dis., 19 (11) (2019), pp. 1181-1190.
5. Navarro M, Camprubí D, Requena-Méndez A, Buonfrate D, Giorli G, Kamgno J, Gardon J, Boussinesq M, Muñoz J, Krolewiecki A. Safety of high-dose ivermectin: a systematic review and meta-analysis. J Antimicrob Chemother. 2020 Apr 1;75(4):827-834. doi: 10.1093/jac/dkz524. PMID: 31960060.
6. Jean SS, Lee PI, Husueh PR. Treatment options for COVID-19: the reality and challenges. J Microbiol Immunol Infect. 2020;53(3): 436–43.
7. PAHO. Ongoing living update of COVID-19 therapeutic options: summary of evidence, 2021. Available: https://iris.paho.org/bitstream/handle/10665.2/52719/PAHOIMSEIHCOVID-19200030_eng.pdf?sequence=17&isAllowed=y.
8. Clinical Trial. Prophylactic ivermectin in COVID-19 contacts.. Available: https://clinicaltrials.gov/ct2/show/NCT04422561.
9. Clinical Trial. Clinical trial of ivermectin plus doxycycline for the treatment of confirmed Covid-19 infection. Available: https://clinicaltrials.gov/ct2/show/NCT04523831.
10. Hashim HA, Maulood MF, Rasheed AM. Controlled randomized clinical trial on using ivermectin with doxycycline for treating COVID-19 patients in Baghdad, Iraq. medRxiv 2020:2020.10.26.20219345.
11. Kim MS, An MH, Kim WJ, et al. Comparative efficacy and safety of pharmacological interventions for the treatment of COVID-19: a systematic review and network meta-analysis. PLoS Med 2020;17:e1003501. doi:10.1371/journal.pmed.1003501 pmid:http://www.ncbi.nlm.nih.gov/pubmed/33378357.
12. Kow CS, Merchant HA, Mustafa ZU, Hasan SS. The association between the use of ivermectin and mortality in patients with COVID-19: a meta-analysis [published online ahead of print, 2021 Mar 29]. Pharmacol Rep. 2021;1-7. doi:10.1007/s43440-021-00245-z.
13. Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter JJ. Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019: The Ivermectin in COVID Nineteen Study. Chest. 2021;159(1):85-92. doi:10.1016/j. chest.2020.10.009.
14. Nurullah Okumus, Nese Demirtürk, Rıza Aytac et al. Evaluation of the effectiveness and safety of adding ivermectin to treatment in severe COVID-19 patients. BMC Infectious Diseases (2021) 21:411.
15. Waheed M Shoumann, Abdelmonem Awad Hegazy, Ramadan M Nafae et al. Use of Ivermectin as a Potential Chemoprophylaxis for COVID-19 in Egypt: A Randomized Clinical Trial. Journal of Clinical and Diagnostic Research. 2021 Feb, Vol-15(2): OC27-OC32.
16. Andrew Bryant, Theresa A Lawrie, Therese Dowswell, Edmund Fordham, Scott Mitchell, Sarah Hill and Tony Tham. Ivermectin for Prevention and Treatment of COVID-19 Infection: a Systematic Review and Meta-analysis. Research square at https://assets.researchsquare.com/files/rs-317485/v1/611bf808-b0eb-4a9a-b877-6d6cc8f79d54.pdf.
17. Eduardo López-Medina et al. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19. A Randomized Clinical Trial. JAMA. 2021;325(14):1426-1435. doi:10.1001/jama.2021.3071.
18. WHO Therapeutics and COVID-19 living guideline at https://app.magicapp.org/#/guideline/5058/section/67421.
19. Ivermectin for COVID-19: real-time meta-analysis of 58 studies at https://ivmmeta.com/.
20. Chaccour C, Casellas A, Blanco-Di Matteo A, et al. The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: a pilot, double-blind, placebo-controlled, randomized clinical trial. EClinicalMedicine 2021;32:100720.doi:10.1016/j.eclinm.2020.100720.
21. Hill A, Abdulamir A, Ahmed S. Meta-Analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection. Research square 2021.doi:10.21203/rs.3.rs-148845/v1.
22. Garegnani LI, Madrid E, Meza NMisleading clinical evidence and systematic reviews on ivermectin for COVID-19BMJ Evidence-Based Medicine Published Online First: 22 April 2021. doi: 10.1136/bmjebm-2021-111678.

                Talus dislocations

                                     DR KS Dhillon

Anatomy of the talus

The talus is the second largest tarsal bone, and it is situated posteriorly in the hindfoot between the tibia and the calcaneus. Two-thirds of the talar surface is covered with articular cartilage and it has a tenuous blood supply. It has 5 articular surfaces and there are no muscles or tendons attached to it. The talus has 3 parts, namely the head, neck, and body. There are two processes on the talus (the lateral and posterior process).

The talus has seven articular surfaces.

Superiorly the talus through the talar dome forms the mortise joint of the ankle with the tibia, medial and lateral malleoli.

Inferoposteriorly there is a large oblique facet that is concave which articulates with the calcaneus to form the talocalcaneal joint.

Anteroinferiorly there are two facets that articulate with the calcaneus to form part of the talocalcaneonavicular joint. The talar head articulates anteriorly with the navicular to form the talonavicular joint.

Blood supply is provided by the posterior tibial artery into the medial side of body and sinus, anterior tibial artery/dorsalis pedis artery into head and neck, and peroneal artery into the lateral side of the body and sinus. 

Robust peritalar ligaments provide stability to the talus. These include:

• Anterior talofibular ligament
• Posterior talofibular ligament
• Talocalcaneal ligaments
• Tarsal sinus ligaments
• Cervical ligament
• Talocalcaneal interosseous ligament
• Deltoid ligament
• Anterior tibiotalar ligament
• Posterior superficial tibiotalar ligament
• Posterior deep tibiotalar ligament
• Dorsal talonavicular ligament

Talus dislocation

There several types of talar dislocation given its multiple articulations. These include tibiotalar dislocation, subtalar dislocation, total talar dislocation, and talonavicular dislocation.

1.Total talar dislocation.

Total talar dislocation is also known as extrusion of the talus or pan-talar dislocation. It involves a tri-articular dislocation of the talus at the tibiotalar, talonavicular, and subtalar joints.  Most injuries are compound.

It usually occurs due to a high‐energy impact to an inverted, plantar‐flexed foot resulting from a fall from height or from a motor vehicle accident.

Total dislocation of the talus is a rare injury and it accounts for only 0.06% of all dislocations and only 2% of talar injuries [1]. 

Limited blood supply and numerous articulations of the talus along with the fact that the injuries are frequently open, make the treatment of total talar dislocation difficult. Such injuries are often associated with complications such as avascular necrosis (AVN), infection, and osteoarthritis [2]. 

In patients with close dislocation, a close reduction is carried out under GA and if the reduction is stable a cast is applied for 6 weeks. If the reduction is not stable percutaneous pinning can be carried out to maintain the talus in its position. If a close reduction is not successful, open reduction is carried out.

In patients with open dislocation, wound irrigation, debridement, and temporary internal or external stabilization of the ankle is carried out.

If the talus is lost and cannot be found, tibiocalcaneal fusion and fibular graft is a surgical option.

Primary talectomy is not recommended. All attempts must be made to preserve the talus even in patients with total extrusion of the talus with significant contamination.

Besides the total dislocation of the talus, neurovascular, capsular, and ligamentous injuries and pressure necrosis are early concomitant injuries.  Late complications include AVN, infection, and post-traumatic degenerative arthritis. Post-traumatic osteoarthritis can occur after several years. 

Incidence of AVN after total dislocation of the talus varies between 24% [3] and 88% [4]. The incidence of posttraumatic osteoarthritis (PT) varies between 10% [3] and 44% [4].

Open talar dislocations are often complicated by soft‑tissue infection. The incidence of infection ranges from 11.5% to 38% [5,6]. Infection rate as high as 88.9% has been reported in the older days [7]. Over the years, infection rates have been brought down through improvement of staged procedures for wound care and soft‑tissue management and adapted antibiotherapy.

2.Subtalar Dislocation

Subtalar dislocations are also known as peritalar dislocations. Subtalar dislocation is a rare injury that accounts for 1%–2% of all dislocations. In subtalar dislocations, there is a separation of the talonavicular and talocalcaneal articulations. These dislocations are commonly caused by falls from height, motor vehicle crashes, and twisting leg injuries. The dislocations are divided into anterior, posterior, medial, and lateral types based on the direction in which the distal part of the foot moves in relation to the talus. The most common type is medial dislocation which results from an inversion injury. A medial dislocation occurs in about 71.5 % of the patients, lateral in 26.0%, posterior in 1.6%, and anterior in about 0.8% of the patients [8]. Most of the dislocations are close. An open dislocation occurs in about 22.5% of the patients [8]. Sometimes subtalar dislocations are associated with fractures of the navicular, calcaneus, and talus. Additional bony injury is seen in about 61.4% of the patients [8].

During the physical examination, the neurovascular status must be carefully assessed. Subtalar dislocations are treated with closed reduction under sedation. In about 14% of the patients close reduction is unsuccessful. If close reduction fails, immediate open reduction should be carried out. After reduction of the dislocation, X-rays and if necessary computed tomography scan should be performed to evaluate the alignment of the bones and evaluate the presence of fractures.

The overall outcome of treatment of subtalar dislocations is good in 52.3%, fair in 25.2%, and poor in 22.5% of the patients.

The most frequent late complications following subtalar dislocations include pain, decreased motion, subtalar instability, and degenerative joint disease [9,10]. Other complications that have been reported include avascular necrosis of the talus, RSD (reflex sympathetic dystrophy), and recurrent dislocation [11]. Some authors have reported no AVN following subtalar dislocations [11,12] while others have reported a low incidence of 4% to 6% [9,10]. In patients with severe open fracture-dislocations of the subtalar joint a high incidence of 33% has been reported [13].

About 80% of patients with subtalar dislocation show significant restriction of motion and about 30% show roentgenographic evidence of arthritis [14].

3.Talonavicular Dislocation

Isolated dislocation of the talonavicular joint is a rare injury. These injuries are caused by severe adduction or abduction force applied to the forefoot. 

A medially or laterally directed force applied to the foot causes dislocation of the talonavicular joint without dislocation of the subtalar joint. The calcaneum along with the remaining foot swivels on the intact interosseous talocalcaneal ligament. The dislocation can be medial or lateral depending on the direction of the force applied to the foot. Medial dislocation is more common than a lateral dislocation.

The dislocation is treated by close reduction and cast immobilization. If close reduction fails, an open reduction is carried out, and if the reduction is not stable, internal fixation with K-wires can be done. The leg is immobilized with a cast. 

4.Tibiotalar dislocation

The tibiotalar joint is formed by the tibia, fibula, and talus. Stability is provided by the strong medial (deltoid) and lateral ligaments.

Tibiotalar dislocation is also known as talocrural or ankle dislocation. Tibiotalar dislocations without associated fractures are very uncommon. More than 50% of these dislocations are posteromedial and 25% are pure posterior dislocations [15]. The majority of dislocations are open injuries. On rare occasions, the dislocation can be anterior/anterolateral, medial, or lateral.

The usual mechanism of injury is a fall on a fully plantarflexed foot. The fall forces the talus into a position posterior to the tibia. Other causes of dislocation include motor vehicle accidents and sporting injuries. 

Most cases of closed tibiotalar dislocations can be treated by close reduction under sedation and cast immobilization for 6 to 9 weeks [15].  Open injuries are treated with thorough wound lavage and débridement followed by reduction of the dislocation, stabilization with K-wires if necessary, repair of ligaments and capsule, and immobilization in a slab followed by casting.

The overall prognosis for tibiotalar dislocations is favorable. The majority of patients are asymptomatic following appropriate treatment [16]. Those who are symptomatic (primarily female) complain of ankle stiffness. Ankle instability is rare. Closed dislocations are associated with fewer symptoms as compared to open dislocations. Some of the prognostic factors that are associated with worse outcomes include advanced age, presence of vascular injury, delay in reduction, and inferior tibiofibular ligament injury [16].  Late complications reported include stiffness, degenerative changes, joint instability, and capsular calcification [17]. 

The incidence of posttraumatic osteoarthritis is about 25% and it often occurs in patients with open dislocations [18]. 

Conclusion

There several types of talar dislocation given its multiple articulations. These include tibiotalar dislocation, subtalar dislocation, total talar dislocation, and talonavicular dislocation. Most of the time these dislocations result from falls from a height. Other causes include motor vehicle accidents and sports injuries. 

The injuries can be open or close. Open dislocations are treated with wound debridement. The dislocation can be treated with close reduction. If close reduction fails open reduction can be carried out. If the reduction is stable the limb is immobilized with a cast for 6 to 8 weeks. If the reduction is not stable then the fragments can be stabilized with k-wires or external fixation.

The complications include loss of motion, instability, AVN, and posttraumatic arthritis. Generally, the clinical outcome is good. Open dislocations can result in poorer outcomes.

Reference

1. Pavić R. Talocalcaneal transfixation in total dislocation of the talus and subtalar dislocations. Mil Med, 2009, 174: 324–327.
2. Wagner R, Blattert TR, Weckbach A. Talar dislocations. Injury. 2004 Sep;35 Suppl 2:SB36-45. doi: 10.1016/j.injury.2004.07.010. PMID: 15315877.
3. Weston JT, Liu X, Wandtke ME, Liu J, Ebraheim NE. A systematic review of total dislocation of the talus. Orthop Surg. 2015;7(2):97-101. doi:10.1111/os.12167.
4. Boden, Kaeleen A. BA1; Weinberg, Douglas S. MD1; Vallier, Heather A. MD1, a Complications and Functional Outcomes After Pantalar Dislocation, The Journal of Bone and Joint Surgery: April 19, 2017 - Volume 99 - Issue 8 - p 666-675 doi: 10.2106/JBJS.16.00986.
5. Palomo-Traver JM, Cruz-Renovell E, Granell-Beltran V, Monzonís-García J. Open total talus dislocation: Case report and review of the literature. J Orthop Trauma 1997;11:45-9.
6. Marsh JL, Saltzman CL, Iverson M, Shapiro DS. Major open injuries of the talus. J Orthop Trauma 1995;9:371-6.
7. Detenbeck LC, Kelly PJ. Total dislocation of the talus. J Bone Joint Surg Am. 1969 Mar;51(2):283-8. PMID: 4975068.
8. Hoexum F, Heetveld MJ. Subtalar dislocation: two cases requiring surgery and a literature review of the last 25 years. Arch Orthop Trauma Surg. 2014 Sep;134(9):1237-49. doi: 10.1007/s00402-014-2040-6. Epub 2014 Jul 4. PMID: 24993588.
9. Christensen SB, Lorentzen JE, Krogsøe O, Sneppen O. Subtalar dislocation. Acta Orthop Scand. 1977;48(6):707-11. doi: 10.3109/17453677708994821. PMID: 607761.
10. Zimmer TJ, Johnson KA. Subtalar dislocations. Clin Orthop Relat Res. 1989 Jan;(238):190-4. PMID: 2910600.
11. F. Rivera, C. Bertone, E. Crainz, P Maniscalco and M. Filisio. Peritalar dislocation: three case reports and literature review. J Orthopaed Traumatol (2003) 4:39–44.
12. Wang HY, Wang BB, Huang M, Wu XT. Treatment of closed subtalar joint dislocation: A case report and literature review. Chin J Traumatol. 2020;23(6):367-371. doi:10.1016/j.cjtee.2020.08.008
13. Goldner JL, Poletti SC, Gates HS 3rd, Richardson WJ. Severe open subtalar dislocations. Long-term results. J Bone Joint Surg Am. 1995 Jul;77(7):1075-9. doi: 10.2106/00004623-199507000-00015. PMID: 7608231.
14. Heppenstall RB, Farahvar H, Balderston R, Lotke P. Evaluation and management of subtalar dislocations. J Trauma. 1980 Jun;20(6):494-7. doi: 10.1097/00005373-198006000-00011. PMID: 7373681.
15. Grotz et al. Open Tibiotalar Dislocation Without Associated Fracture in a 7-Year-Old Girl. A Case Report & Literature Review. Am J Orthop. 2008;37(6): E116-E118.
16. Wight L, Owen D, Goldbloom D, Knupp M. Pure Ankle Dislocation: A systematic review of the literature and estimation of incidence. Injury. 2017 Oct;48(10):2027-2034. 
17. Wang YT, Wu XT, Chen H. Pure closed posteromedial dislocation of the tibiotalar joint without fracture. Orthop Surg. 2013 Aug;5(3):214-8.
18. Elisé S, Maynou C, Mestdagh H, Forgeois P, Labourdette P. Les luxations tibio-astragaliennes pures. A propos de 16 observations [Simple tibiotalar luxation. Apropos of 16 cases]. Acta Orthop Belg. 1998 Mar;64(1):25-34. French. PMID: 9586247.

Distal Humerus Fractures

                        Distal Humerus Fractures
  

                                        Dr. KS Dhillon

Introduction

Fractures of the distal humerus constitute about 2% of all fractures in the adult population [1]. The overall incidence of distal humeral fractures in adults is 5.7 cases per 100,000 in the population per year. The male to female ratio is about equal. There is a bimodal age distribution with the first peak in young individuals resulting from high-energy trauma and the second peak in the elderly osteoporotic population. Two-thirds of those affected are aged 50 years or older. The incidence of these fractures is rising. 

Simple falls are the most common overall cause of the fracture, and the majority of the fractures are extra-articular or complete articular fractures [2]. 

The aim of treatment is to restore a functional elbow in the functional range of motion between 30 to 130 degrees [3]. Loss of elbow movements can severely affect activities of daily living and lead to a loss of independence, especially in elderly individuals [4]. Treatment of these fractures can be challenging due to fracture comminution, poor bone quality as well as difficulty in restoring the complex anatomy of the distal humerus [5].

Most of the distal humerus fractures used to be treated non-operatively in the past and the treatment often resulted in significant functional impairment [2]. 

However, with evolution in implant design and surgical technique, the outcome of operative treatment has improved and this has made internal fixation of the fractures as the current standard of care. The aim of surgical treatment is to restore articular congruity and bony alignment while providing rigid, stable fixation that enables early active motion [6]. 

         

Anatomy of Distal Humerus

In the coronal plane, the distal humerus is triangular in shape. It is formed by the medial and lateral columns which are linked by the articular segment as shown in Fig.1. 

The distal end of the humerus includes two smooth articular surfaces (capitulum and trochlea), two depressions (fossae) that form part of the elbow joint, and two projections (medial and lateral epicondyles). The capitulum laterally articulates with the radius; the trochlea, a spool-shaped surface, articulates with the ulna. The articular surface is in 4-8 degrees of valgus relative to the shaft and flexed 40 degrees relative to the shaft.

               

                                                        Fig 1. Anatomy of distal Humerus

Classification of Distal Humerus Fracture

The AO classification divides distal humeral fractures into three groups namely, A, B, and C with complexity and severity increasing.

Müller’s classification of distal humeral fracture is part of the AO scheme. This region is marked 13, so each type has this prefix, e.g. 13-A1.

Type Description

Type A:   Extraarticular fractures:

13-A1:    Apophyseal avulsion

13-A2:    Metaphyseal simple

13-A3:    Metaphyseal multifragmentary (comminuted)

Type B:    Partial articular fractures:

13-B1:     Sagittal lateral condyle

13-B2:     Sagittal medial condyle

13-B3:     Frontal

Type C:   Complete articular fractures:

13-C1:     Articular simple, metaphyseal simple

13-C2:     Articular simple, metaphyseal multifragmentary (comminuted)

13-C3:     Articular, multifragmentary (comminuted)

Imaging for Distal Humerus Fractures

All attempts are made to obtain good-quality radiographs. This may be difficult due to patient discomfort. The AP is taken with the elbow flexed to 40 degrees. This facilitates olecranon disengagement from the fossa which allows for better visualization of the distal humerus. The lateral images are taken with the shoulder abducted to 90 degrees and the elbow flexed to 90 degrees with the plate underneath the medial aspect of the elbow. A CT scan is useful to assess articular involvement and aid surgical planning. 

Non-Operative Treatment

Over the decades, there are only a few conflicting reports available in the literature on the outcomes of conservatively treated fractures of the distal humerus. Non-operative treatment involves splintage for pain relief followed by gentle mobilization. 

Nauth et al [7] showed that in elderly patients, those treated non-operatively were almost three times more likely to have an unacceptable result as compared to those treated operatively. Non-operative treatment is usually reserved for undisplaced fractures, for patients with dementia, and those who are not fit for anesthesia. Recently Aitken et al. reported that non-operative treatment could give a modest functional result in low-demand patients while avoiding substantial surgical risks [8].

Operative treatment 

Distal humerus fractures are commonly treated by surgery if the fracture is displaced and the patient is fit for surgery.

There are three surgical approaches to the distal humerus, namely the triceps reflecting, triceps splitting, and the trans-olecranon approach. The trans-olecranon approach gives the best articular exposure but it carries the risk of non-union, future need for the removal of implants, and potentially limiting any future arthroplasty. 

The triceps splitting approach has the potential to result in triceps weakness. The triceps reflecting technique spares the triceps mechanism and has the advantage of avoiding damage to the extensor mechanism. This approach, however, provides limited exposure of the articular surface.

For complex intra-articular fractures (type C), an olecranon osteotomy is usually preferred.

The aim of treatment is to obtain anatomic reduction and rigid internal fixation which will allow early mobilization. Rigid plate fixation gives better functional outcomes as compared to fixation solely with Kirschner wires or screws [9]. Plate fixation is now the standard treatment for distal humerus fractures. Although perpendicular plating was originally advocated by the AO group, parallel plating has now grown in popularity. Studies have shown that parallel plating provides better stability compared with the perpendicular locking system [10,11]. Clinical studies show there are no differences between the groups (perpendicular and parallel plates) in terms of functional outcome or complication rate [12,13]. The use of locking compression plates has been advocated for osteoporotic fractures as they provide angular stability and the head-locking mechanism potentially results in a stiffer construct [24]. 

Different length plates are used for fracture fixation to avoid a stress riser at the end of the plates and avoid the risk of a peri-prosthetic fracture. Post-operatively a back slab used for one to two weeks to protect the wound. Passive mobilization is carried out from two weeks and active mobilization after six weeks.

Despite the improvements in surgical techniques and evolution of implant designs, operative fixation of distal humerus fractures have been associated with dissatisfaction in about 15% of patients and complication rates of up to 35% [14,15]. Some of the factors that are known to affect clinical outcome include fracture comminution, reduction accuracy, fixation stability, and quality of postoperative rehabilitation [16]. 

Complications of operative treatment of distal humerus fracture

Complications can include hardware failure, fracture, malunion, non-union, infection, heterotopic ossification, elbow stiffness, ulnar neuropathy, and complications from olecranon osteotomy [17].

• Mechanical failure-- Mechanical failure is known to occur in 7–27% of patients [18,19,20]. Risk factors for failure include bone quality, such as osteoporotic or osteopenic bone, the complexity of the fracture,  bone defects, mechanical properties of implants, and postoperative rehabilitation [21]. Poor surgical technique is another risk factor. 
• Ulnar neuropathy-- Ulna neuropathy as a complication of distal humerus fractures, preoperatively and/or postoperatively, occurs in 0% to 51% of the patients, with an average of 13% [17]. The palsy can occur either at the time of the injury or intraoperatively. It can also occur secondarily due to swelling, to scar tissue development and thickening in the fibro-osseous tunnel, or due to hardware irritation. The true incidence of ulnar nerve dysfunction after elbow injury remains unknown. It appears that anterior transposition of the ulna nerve does not decrease the development of ulnar neuropathy after internal fixation of the fracture [17]. 
• Heterotopic ossification--The incidence of heterotopic ossification (HO) after internal fixation of distal humerus fractures varies widely from 0% to 49%. However, pooled analysis of data from several studies shows an overall prevalence of 8.6% [17]. There are several risk factors for HO and these include, concomitant head and central nervous system injury, delayed internal fixation,33 use of bone graft or substitute, prolonged postoperative immobilization. A 48 hours delay in fixation can increase the rate of HO from 0% to 33%. Kundel et al reported an increase in the rate of HO from 29% to 80% when surgical treatment was delayed by more than 24 hours [22]. HO can be radiologically visible two weeks after surgery in 86% of patients who finally developed HO [23]. In some cases, HO can cause limitations in elbow motion and function, and in such patients excision of the HO may be necessary. The routine use of indomethacin for prophylaxis against HO following internal fixation of distal humerus fractures remains controversial.
• Elbow stiffness-- Elbow stiffness is the most common sequela after internal fixation of distal humeral fractures. Elbow stiffness can be often seen even after optimal stable fixation and proper rehabilitation. Some authors have reported that one-third of patients failed to get a functional range of motion in the elbow after fracture fixation [17]. Loss of elbow motion can result from intrinsic or extrinsic causes such as malunion, nonunion, incongruity of the articular surface, intra-articular and capsular fibrosis, and adhesions around the elbow callus formation, HO, prolonged postoperative immobilization, and prominent hardware [24]. Early mobilization remains the mainstay of the prevention of elbow stiffness. In some patients, surgical treatment of elbow stiffness is needed. In these patients arthrolysis and contracture release is necessary. Open release of elbow stiffness is usually more effective when HO is obstructing motion. Sometimes implants need to be removed. Sometimes refractures can occur after the removal of implants.
• Nonunion-- Nonunions after internal fixation of distal humerus fractures have been reported to be between 2% and 10% [25].  High-energy trauma, gross comminution, and poor bone stock are some of the reasons for nonunion. In elderly patients, fracture union rather than motion is the first priority, because motion can be restored later by contracture release after the fracture unites. Nonunions can severely compromise the patient’s quality of life [26]. Nonunions usually need revision of internal fixation, autogenous bone-grafting, and aggressive contracture release.
• Malunion-- Malunion is seen in about 30% of patients with distal humerus fractures. It is more common in patients with nonoperatively treated fractures as compared to operatively treated fractures. Malunions of the distal humerus are either extra-articular or intra-articular. Extra-articular malunions are treated with humeral osteotomy and fixation. Intra-articular malunions are more difficult to treat. Intra-articular corrective osteotomy is usually considered in young patients who present with moderate to severe functional disability and/or pain and secondary post-traumatic arthritis at an early stage [27]. The aim of treatment is to restore the articular anatomy in order to improve motion, relieve pain and enhance stability in active young patients. In the elderly low demand patients, a total elbow replacement is an option.
• Infection and wound complications--  The wound complications incidence after fixation of distal humerus fractures is substantial and can be associated with significant morbidity. The risk for serious wound complications after surgery is high because of soft tissue damage, relatively thin soft tissue envelope, postoperative swelling, and shear forces occurring when elbow motion is started [28].     Infection should be suspected in any patient with persistent wound discharge. Open fractures and the use of a plate to stabilize the olecranon osteotomy, are considered to be significant risk factors. Majority of wound complications can successfully be treated with debridement and primary or delayed wound closure. In some patients, myocutaneus flaps may be necessary.
• Failure of olecranon osteotomy-- Complications of olecranon osteotomy include nonunion, malunion, hardware failure, and skin irritation by prominent implants. The incidence of complications associated with olecranon osteotomy ranges from 0% to 31% [17]. The reported rate of nonunion is about 11.9% [29].

Elbow Arthroplasty

Total elbow arthroplasty (TEA) is being increasingly used for the treatment of comminuted intra-articular distal humerus fractures in the elderly patients [30]. Because of its limited longevity due to aseptic loosening, TEA is only recommended in patients with sedentary lifestyles who can comply with the post-operative rehabilitation program [5].  A study by Prasad et al showed that survivorship of the implants, with revision and definite loosening as end-points, was 89.5% at ten years in those patients who were followed for a minimum of ten years [31]. 

A study by Mansat et al [32] which analyzed the outcome of treatment of 87 patients over the age of 65 with a distal humeral fracture treated who were treated with TEA found that 63% of patients had a pain free elbow at 37.5 months follow up, 48% had a mean flexion-extension arc of at least 100º, and 79% of the patients had normal function. 

There were complications in 23% of the patients and revision surgery was necessary for 9% of the patients. 

Conclusion

Fractures of the distal humerus constitute about 2% of all fractures in the adult population. The overall incidence of distal humeral fractures in adults is 5.7 cases per 100,000 in the population per year. Distal humerus fractures are difficult to treat especially in the elderly with poor bone stock. Improvements in implant design and surgical technique have resulted in better clinical outcomes following open reduction and internal fixation of distal humerus fractures. Open reduction and internal fixation is now standard treatment for displaced fractures of the distal humerus. 

However, the open reduction and internal fixation of these fractures can be challenging and can be associated with a high rate of complications. Total elbow arthroplasty has been advocated as a treatment option for elderly patients especially in those with unreconstructable distal humerus fractures.

References

1. Frankle M.A., Herscovici D., Jr, DiPasquale T.G., Vasey M.B., Sanders R.W. A comparison of open reduction and internal fixation and primary total elbow arthroplasty in the treatment of intraarticular distal humerus fractures in women older than age 65. J. Orthop. Trauma. 2003;17(7):473–480.
2. Robinson CM, Hill RM, Jacobs N, Dall G, Court-Brown CM. Adult distal humeral metaphyseal fractures: epidemiology and results of treatment. J Orthop Trauma. 2003 Jan;17(1):38-47. doi: 10.1097/00005131-200301000-00006. PMID: 12499966.
3. Morrey B.F., Askew L.J., Chao E.Y. A biomechanical study of normal functional elbow motion. J. Bone Joint Surg. Am. 1981;63(6):872–877. doi: 10.2106/00004623-198163060-00002. 
4. McKee M.D., Jupiter J.B. Fractures of the distal humerus. 3 rd ed. Philadelphia: Lippincott: Skeletal trauma.; 2002. pp. 765–782.
5. Beazley JC, Baraza N, Jordan R, Modi CS. Distal Humeral Fractures-Current Concepts. Open Orthop J. 2017;11:1353-1363. Published 2017 Nov 30. doi:10.2174/1874325001711011353.
6. Gabel G.T., Hanson G., Bennett J.B., Noble P.C., Tullos H.S. Intraarticular fractures of the distal humerus in the adult. Clin. Orthop. Relat. Res. 1987;(216):99–108.
7. Nauth A, McKee MD, Ristevski B, Hall J, Schemitsch EH. Distal humeral fractures in adults. J. Bone Joint Surg. Am. 2011;6(93)(7):686–700.
8. Aitken SA, Jenkins PJ, Rymaszewski L. Revisiting the 'bag of bones': functional outcome after the conservative management of a fracture of the distal humerus. Bone Joint J. 2015 Aug;97-B(8):1132-8. doi: 10.1302/0301-620X.97B8.35410. PMID: 26224833.
9. Papaioannou N., Babis G.C., Kalavritinos J., Pantazopoulos T. Operative treatment of type C intra-articular fractures of the distal humerus: The role of stability achieved at surgery on final outcome. Injury. 1995;26(3):169–173.
10. Stoffel K., Cunneen S., Morgan R., Nicholls R., Stachowiak G. Comparative stability of perpendicular versus parallel double-locking plating systems in osteoporotic comminuted distal humerus fractures. J. Orthop. Res. 2008;26(6):778–784. doi: 10.1002/jor.20528. 
11. Arnander M.W., Reeves A., MacLeod I.A., Pinto T.M., Khaleel A. A biomechanical comparison of plate configuration in distal humerus fractures. J. Orthop. Trauma. 2008;22(5):332–336. doi: 10.1097/BOT.0b013e31816edbce.
12. Shin S.J., Sohn H.S., Do N.H. A clinical comparison of two different double plating methods for intraarticular distal humerus fractures. J. Shoulder Elbow Surg. 2010;19(1):2–9. doi: 10.1016/j.jse.2009.05.003. 
13. Lee S.K., Kim K.J., Park K.H., Choy W.S. A comparison between orthogonal and parallel plating methods for distal humerus fractures: A prospective randomized trial. Eur. J. Orthop. Surg. Traumatol. 2014;24(7):1123–1131. doi: 10.1007/s00590-013-1286-y. 
14. Holdsworth B.J., Mossad M.M. Fractures of the adult distal humerus. Elbow function after internal fixation. J. Bone Joint Surg. Br. 1990;72(3):362–365. 
15. John H., Rosso R., Neff U., Bodoky A., Regazzoni P., Harder F. Operative treatment of distal humeral fractures in the elderly. J. Bone Joint Surg. Br. 1994;76(5):793–796.
16. Zhang C, Zhong B, Luo CF. Comparing approaches to expose type C fractures of the distal humerus for ORIF in elderly patients: six years clinical experience with both the triceps-sparing approach and olecranon osteotomy. Arch Orthop Trauma Surg. 2014 Jun;134(6):803-11. doi: 10.1007/s00402-014-1983-y. Epub 2014 Apr 29. PMID: 24777538.
17. Savvidou OD, Zampeli F, Koutsouradis P, et al. Complications of open reduction and internal fixation of distal humerus fractures. EFORT Open Rev 2018;3:558-567. DOI: 10.1302/2058-5241.3.180009.
18. Pereles TR, Koval KJ, Gallagher M, Rosen H. Open reduction and internal fixation of the distal humerus: functional outcome in the elderly. J Trauma 1997;43:578–584.
19. Frankle MA, Herscovici D, Jr, DiPasquale TG, Vasey MB, Sanders RW. A comparison of open reduction and internal fixation and primary total elbow arthroplasty in the treatment of intraarticular distal humerus fractures in women older than age 65. J Orthop Trauma 2003;17:473–480. 
20. Kaiser T, Brunner A, Hohendorff B, Ulmar B, Babst R. Treatment of supra- and intra-articular fractures of the distal humerus with the LCP Distal Humerus Plate: a 2-year follow-up. J Shoulder Elbow Surg 2011;20:206–212.
21. Obert L, Ferrier M, Jacquot A, et al. Distal humerus fractures in patients over 65: complications. OTSR 2013;99:909–913.
22. Kundel K, Braun W, Wieberneit J, Ruter A. Intraarticular distal humerus fractures: factors affecting functional outcome. Clin Orthop Relat Res 1996;332:200–208.
23. Abrams GD, Bellino MJ, Cheung EV. Response to letter to editor regarding ‘Risk factors for development of heterotopic ossification of the elbow after fracture fixation’. J Shoulder Elbow Surg 2013;22:e31.
24. Green A. Postoperative management after open reduction and internal fixation of distal humeral fractures. Instr Course Lect 2009;58:535–539.
25. Helfet DL, Kloen P, Anand N, Rosen HS. Open reduction and internal fixation of delayed unions and nonunions of fractures of the distal part of the humerus. J Bone Joint Surg [Am] 2003;85-a:33–40.
26. Mighell MA, Stephens B, Stone GP, Cottrell BJ. Distal Humerus Fractures: Open Reduction Internal Fixation. Hand Clin. 2015 Nov;31(4):591-604. doi: 10.1016/j.hcl.2015.06.007. Epub 2015 Aug 25. PMID: 26498548.
27. McKee M, Jupiter J, Toh CL, Wilson L, Colton C, Karras KK. Reconstruction after malunion and nonunion of intra-articular fractures of the distal humerus. Methods and results in 13 adults. J Bone Joint Surg Br. 1994 Jul;76(4):614-21. PMID: 8027152.
28. Choudry UH, Moran SL, Li S, Khan S. Soft-tissue coverage of the elbow: an outcome analysis and reconstructive algorithm. Plast Reconstr Surg. 2007 May;119(6):1852-1857. doi: 10.1097/01.prs.0000259182.53294.67. PMID: 17440365.
29. Henley MB, Bone LB, Parker B. Operative management of intra-articular fractures of the distal humerus. J Orthop Trauma. 1987;1(1):24-35. doi: 10.1097/00005131-198701010-00004. PMID: 3506583.
30. Rajaee SS, Lin CA, Moon CN. Primary total elbow arthroplasty for distal humeral fractures in elderly patients: a nationwide analysis. J Shoulder Elbow Surg. 2016 Nov;25(11):1854-1860. doi: 10.1016/j.jse.2016.05.030. Epub 2016 Aug 12. PMID: 27528540.
31. Prasad N, Ali A, Stanley D. Total elbow arthroplasty for non-rheumatoid patients with a fracture of the distal humerus: a minimum ten-year follow-up. Bone Joint J. 2016 Mar;98-B(3):381-6. doi: 10.1302/0301-620X.98B3.35508. PMID: 26920964.
32. Mansat P, Nouaille Degorce H, Bonnevialle N, Demezon H, Fabre T; SOFCOT. Total elbow arthroplasty for acute distal humeral fractures in patients over 65 years old - results of a multicenter study in 87 patients. Orthop Traumatol Surg Res. 2013 Nov;99(7):779-84. doi: 10.1016/j.otsr.2013.08.003. Epub 2013 Oct 3. PMID: 24095596.

                     

             Antibiotic use in Hospitals

                                           Dr. KS Dhillon

Introduction

The last 60 plus years have witnessed the golden age of antibiotic discovery and their widespread use in hospitals. Many of the antibiotics available are regarded as very effective, safe, and relatively inexpensive. They have saved millions of lives. This availability of many antibiotics, however, has led to their misuse, leading to bacterial resistance.

There is a need to optimize antimicrobial use so as to slow the spread of resistant pathogens.

There is a dire need for hospitals to implement antimicrobial stewardship programs with the aim of improving antimicrobial use to optimize infection cure rates and minimize harm [1].

Most often efforts to evaluate antimicrobial stewardship programs’ effect on hospital antibiotic use focus on volume rather than prescribing quality [2,3,4]. It is, however, not known whether the volume of antimicrobial use correlates with the appropriateness of antibiotic use [5].

Prescribing decisions for patients in hospitals are associated with several factors, including allergies, comorbidities, adverse effects, and drug interactions.

Evaluating the appropriateness of hospital antimicrobial use is challenging. 

Evaluation of the appropriateness of antibiotic use is lacking in most hospitals. Hospital antimicrobial stewards usually perform intensive, small-scale antibiotic use evaluations to answer specific questions about the appropriateness of antibiotic use. Larger scale evaluations are usually more difficult to conduct.

Inappropriate antibiotic use in hospitals

Antibiotic use in hospitals is common and unfortunately frequently inappropriate. For several decades now it has been known that up to 50% of antimicrobial use is inappropriate [6].

Hecker et al [7] carried out a prospective observational study to evaluate the current pattern of misuse (unnecessary use) of antimicrobials in hospitalized patients. The study included all adult nonintensive care inpatients for whom new antimicrobials were prescribed during a 2-week period. They found that a total of 1941 antimicrobial days of therapy were prescribed for 129 patients. Thirty percent of the therapy was deemed unnecessary.

Administration of antimicrobials for longer than the recommended duration (192 days of therapy) was the most common reason for unnecessary therapy (33%). Other reasons included administration of antimicrobials for noninfectious or nonbacterial syndromes (32%) and treatment of colonizing or contaminating microorganisms (16%). The use of antianaerobic agents accounted for 35% of the unnecessary antimicrobial therapy, and these agents were frequently prescribed when equally efficacious alternative agents with minimal antianaerobic activity were available.

Magill et al [8] carried out a study to assess the appropriateness of antimicrobial use in US hospitals. Their aim was to evaluate the appropriateness of antimicrobial use for patients who were hospitalized for treatment of community-acquired pneumonia (CAP) or urinary tract infection (UTI) present at admission or for patients who had received fluoroquinolone or intravenous vancomycin treatment [8].

They found that overall, treatment was unsupported (inappropriate) for  55.9% of the patients. It was unsupported in 27.3% of the patients who received vancomycin, 46.6% in those who received fluoroquinolones, in 76.8% of those with a diagnosis of UTI, and in 79.5% in those with a diagnosis of CAP. The common reasons for unsupported treatment included excessive duration (59.2% patients with CAP) and lack of documented infection signs or symptoms (50.1% patients with UTI). 

The Australian Commission on Safety and Quality in Health Care in 2018 carried out a Hospital National Antimicrobial Prescribing Survey (NAPS) throughout Australia in both government and private hospitals. The survey showed that antimicrobials with the highest rates of inappropriate prescribing were: cefalexin, cefazolin, azithromycin, amoxicillin-clavulanic acid, and metronidazole. The survey also showed that the five most common indications for prescribing antimicrobials were surgical prophylaxis, community-acquired pneumonia, medical prophylaxis, cystitis, and cellulitis/erysipelas.  The highest proportions of prescriptions assessed as inappropriate were for chronic obstructive pulmonary disease (COPD), surgical prophylaxis, non-surgical wound infections, community-acquired pneumonia, and cystitis [9].

Trivedi et al [10] carried out a multicenter assessment of antibiotic appropriateness in 47 ICUs in the USA. The study included 667 patients in 47 ICUs. Three hundred and two patients (54%) were on antibiotics. The incidence of inappropriate antibiotic use was found to be 31%. The reasons for inappropriate antibiotic use included no infection or nonbacterial syndrome (22%), unnecessarily broad-spectrum (29%), and duration longer than necessary (21%). 

Generally, suboptimal or inappropriate antibiotic prescribing includes overly broad coverage, excessively long treatment, duplicate treatment, failure to de-escalate on the basis of microbiology test results, antimicrobial use when antimicrobials are not required and selection of antimicrobial where the dose, route, or duration is unlikely to treat the pathogen or the likely pathogen [9].

Rising threat of antimicrobial resistance

When antibiotics were first discovered they were called "miracle" drugs which saved millions of lives. Now we face a dramatic challenge as a result of two combined problems. First, bacteria are becoming extremely resistant to existing antibiotics, particularly, Gram-negative rods which are resistant to most of the currently available antibiotics in some settings. Second, there are no new antibiotics in the pipeline [11]. 

In the last few years several new powerful compounds active against Gram-positive cocci have become available, but this is not so for Gram-negative bacteria and there are almost no new antibiotic class active against multiresistant Gram-negative rods. None can be anticipated in the near future. Many doctors are likely to face a therapeutic dead-end in the treatment of certain types of severe bacterial infections. Such a situation will take us back to the pre-antibiotic era of the 1930s and early 1940s [12].

Over the last few years, several alarming facts regarding antimicrobial resistance (AMR) have become known [12]. These include:

• There has been an increase in global resistance rates in many bacterial species such as staphylococci, gonococci, enterococci,  enterobacteria (E. coli, Salmonella, and Shigella), Pseudomonas, Acinetobacter, and Mycobacterium tuberculosis.
• The burden of bacteremias due to E. coli (most common human pathogens) is increasing in Europe, partly due to resistant strains.
• New mechanisms of resistance have emerged and have disseminated. These include extended-spectrum beta-lactamases (ESBL) and carbapenemases. There now exist new resistance genes such as the New Delhi metallo-beta-lactamase 1 (NDM-1) and other carbapenemases in Enterobacteriacae. These "superbugs" are resistant to most available antibiotics and can disseminate around the world very rapidly. 
• Although there has been a rapid increase in the multi-resistance of Gram-negative rods, there has been a steady decrease in methicillin-resistant Staphylococcus aureus (MRSA) rates in many countries due to successful infection control programmes.  In other countries, resistance to both Gram-positive and Gram-negative bacteria is very high. There also other countries with vancomycin-resistant enterococci.
• There is a propensity to use last-line therapy (e.g., carbapenems) to treat infections. This is triggered by a fear of infections caused by ESBL-producing Enterobacteriaceae. These antibiotics should, in fact, be preserved as the last weapons for use against multiresistant Gram-negative bacterias.
• Due to the lack of alternative drugs, old drugs with poor safety and efficacy profiles and uncertain pharmacokinetic/pharmacodynamic characteristics (e.g., colistin) are used.
• Multiresistant bacteria in critically ill patients cause high morbidity and mortality. The European Centre for Disease Prevention and Control (ECDC) reported that in Europe 25,000 people die each year from antibiotic-resistant bacteria [13]. In the USA, there are 90,000 MRSA infections with an estimated 19,000 deaths annually [14].
• Serious financial consequences of bacterial resistance. The healthcare costs and productivity losses due to bacterial resistance is at least 1.5 billion euros each year in Europe [13]. The annual cost of AMR in hospitals in the USA is estimated at more than US$ 20 billion [15]. 

Morbidity, mortality, and the associated economic burden from AMR is very likely to increase dramatically during the next decade [16]. Due to financial crises in many countries in the world, massive cuts in healthcare expenditure and medical research can result in further spread of multiresistant bacteria in hospitals around the world.

The major cause of this frightening evolution is the massive overuse of antibiotics worldwide over the past decades. Excess antibiotics are used particularly for common colds and upper respiratory tract syndromes that are mostly of viral origin. Self-medication, an important driver of antibiotic overuse, is common in many developing countries where antibiotics can be bought over the counter in pharmacies. 

These resistant bacteria can be exchanged via travel activities and patient transfers leading to a rapidly growing "resistance globalization" [12].

At the same time, the antibiotic pipeline is drying up for the following reasons. Firstly it is difficult to find new antibiotics with novel mechanisms of action and secondly a high cost/benefit and risk/benefit ratio discourage pharmaceutical companies from investing in the research and development of new antibiotics. 

Improved diagnosis, education, and legislation can reduce antibiotic consumption. A sustained, multifaceted, community-level intervention can help reduce overall antibiotic use [17]. 

Patients can and should have a very active role in making healthcare safer. In many countries, national campaigns have been launched to educate patients and physicians about antimicrobial misuse and the threat of resistance.

Every hospital should have an antibiotic stewardship program. These programs are dedicated to improving antibiotic use and are commonly referred to as Antimicrobial Stewardship Programs (ASPs). They can both optimize the management of infections and reduce adverse events associated with antibiotic use.

It is important to implement antibiotic stewardship programs around the world. There should be a multidisciplinary approach aimed at the optimal selection, dosage, and duration of antimicrobial treatment that would result in the best clinical outcome for the treatment and prevention of infection with least toxicity to the patient, and least impact on subsequent bacterial resistance. 

Besides the diagnosis, the reason for the prescription and the planned duration of therapy should be indicated on every patient chart. 

An international programme should be able to markedly decrease the overall consumption of antibiotics in humans. There is a need for a strong and sustained cooperation between healthcare professionals and antibiotic users.  All antibiotic prescribers must work together to ensure the success of these programmes.

Strategies for correct antibiotic prophylaxis [18]

Antibiotics alone cannot prevent surgical site infections. Attention to infection and prevention control strategies including correct hand hygiene practices are important strategies to prevent surgical site infections. Other strategies include meticulous surgical techniques and minimization of tissue trauma, clean hospital and operating room environments, proper instrument sterilization processes, targeted glycemic control, and appropriate management of surgical wounds.

Prophylactic antibiotics should be used for operative procedures that have a high rate of postoperative surgical site infection, or when implants are inserted.

Prophylactic antibiotics should be effective against both aerobic and anaerobic bacteria most likely to contaminate the surgical site such as Gram-positive skin commensals or normal flora colonizing the mucosa that is to be incised.

Prophylactic antibiotics should be administered within 120 min prior to the incision. However, for most antibiotics, it is recommended that the first dose should be administered within 30–60 min before the surgical incision is made. This is to ensure an adequate serum and tissue concentration of antibiotics during the period of potential contamination. Obese patients will require higher doses of antibiotics.

A single dose of antibiotic is usually sufficient. Additional antibiotic doses need to be administered intraoperatively for procedures that last more than 2–4 hours and when there is significant blood loss (more than 1.5 L).

There is no evidence that postoperative antibiotic prophylaxis is of any value. Every institution should have guidelines for proper surgical prophylaxis.

Strategies for correct antibiotic therapy [18]

The source of infection should be identified and controlled as soon as possible. Empirical antibiotic therapy should be started after the infection is detected. Microbiological data (culture and sensitivity results) will only be available after 48–72 hours to guide the targeted therapy.

In patients who are critically ill, empiric broad-spectrum therapy which will cover all likely pathogens should be started as soon as possible once the infection is recognized. This empiric antimicrobial therapy should be narrowed once the culture and sensitivity results are available and there is adequate clinical improvement. 

Empirical therapy is chosen based on local epidemiology, clinical severity, individual patient risk factors for multidrug-resistant bacteria, and infection source.

Specimen, for culture and sensitivity, from the site of infection should always be taken for patients with hospital-acquired or with community-acquired infections at risk for resistant pathogens. This would be in patients with previous antimicrobial therapy, prior infection, or colonization with multidrug-resistant pathogens. 

Blood cultures should be taken before the administration of antibiotics in critically ill patients.

The dosages of antibiotics should be optimized to make sure that pharmacodynamic-pharmacokinetic targets are achieved.

The need for and appropriateness of the antibiotic treatment should be reassessed on a daily basis.

Once the source of infection has been controlled, short courses of antibiotic therapy are as effective as longer courses regardless of the fact that signs of inflammation are still present. 

For intra-abdominal infections, 4 days of antibiotics are as effective as 8 days in moderately ill patients [19]. For bloodstream infections, 5 to 7 days of antibiotics are as effective as 7 to 21 days for most patients [20]. For ventilator-associated pneumonia, 8 days of antibiotics are as effective as 15 days [21,22].

When there is failure of antibiotic therapy in patients having active infection a re-operation to clear the infection would be required.

Use of biomarkers such as procalcitonin may be useful to guide the duration and/or cessation of antibiotic therapy in critically ill patients.

The infection prevention and control (IPC) measures combined with ASPs should be implemented in clinical departments. These programs and interventions require regular, systematic monitoring to assess compliance and efficacy.

Antibiotic consumption should be monitored and feedback provided to all ASP team members on a regular basis (e.g. every 3 to 6 months). Data on resistance surveillance and outcome measures should also be provided.

Conclusion

We have overused and abused antibiotics not only in humans but also in animals with huge variations between countries [23]. Now regular and precise barometers to survey resistance levels and antibiotic consumption are available to us [24]. Bacterial resistance to antibiotics has reached levels that place the human race in real danger. There is a worldwide need for immediate, vigorous, and coordinated measures to be taken to save and protect the erosion of existing antibiotics and at the same time facilitate the discovery of new and potent antibiotics, active in particular against Gram-negative bacilli [25,26]. To achieve this there is a need for profound change in the way we diagnose and treat bacterial infections [27]. There is a dire and urgent need for educational programmes targeting both healthcare professionals and consumers, including children. The real key to success is strong cooperation and complicity between healthcare professionals (including researchers) and consumers. 

Reference

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3. Baggs J, Fridkin SK, Pollack LA, Srinivasan A, Jernigan JA. Estimating national trends in inpatient antibiotic use among US hospitals from 2006 to 2012. JAMA Intern Med. 2016; 176(11): 1639-1648. doi:10.1001/jamainternmed. 2016.5651
4. Goodman KE, Cosgrove SE, Pineles L, et al. Significant regional differences in antibiotic use across 576 U.S. hospitals and 11,701,326 million adult admissions, 2016–2017. Clin Infect Dis. 2020;ciaa570. doi:10.1093/cid/ ciaa570.
5. Spivak ES, Cosgrove SE, Srinivasan A. Measuring appropriate antimicrobial use: attempts at opening the black box. Clin Infect Dis. 2016;63(12):1639-1644.
6. Dellit TH, Owens RC, McGowan JE, Jr. et al. IDSA and SHEA Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship. Clin. Infect. Dis. 2007;44:159-77.
7. Hecker MT, Aron DC, Patel NP, Lehmann MK, Donskey CJ. Unnecessary use of antimicrobials in hospitalized patients: current patterns of misuse with an emphasis on the antianaerobic spectrum of activity. Arch Intern Med. 2003 Apr 28;163(8):972-8. doi: 10.1001/archinte.163.8.972. PMID: 12719208.
8. Magill SS, O'Leary E, Ray SM, Kainer MA, Evans C, Bamberg WM, Johnston H, Janelle SJ, Oyewumi T, Lynfield R, Rainbow J, Warnke L, Nadle J, Thompson DL, Sharmin S, Pierce R, Zhang AY, Ocampo V, Maloney M, Greissman S, Wilson LE, Dumyati G, Edwards JR, Chea N, Neuhauser MM; Emerging Infections Program Hospital Prevalence Survey Team. Assessment of the Appropriateness of Antimicrobial Use in US Hospitals. JAMA Netw Open. 2021 Mar 1;4(3):e212007. doi: 10.1001/jamanetworkopen.2021.2007. PMID: 33734417; PMCID: PMC7974639.
9. National Centre for Antimicrobial Stewardship and Australian Commission on Safety and Quality in Health Care. Antimicrobial prescribing practice in Australian hospitals: results of the 2018 Hospital National Antimicrobial Prescribing Survey. Published January 2020.  https://irp-cdn.multiscreensite.com/d820f98f/files/uploaded/Hospital%20NAPS%20Public%20Report%20-%202018.pdf.
10. Trivedi KK, Bartash R, Letourneau AR, et al; Partnership for Quality Care (PQC) Inpatient Antimicrobial Stewardship Working Group. Opportunities to improve antibiotic appropriateness in U.S. ICUs: a multicenter evaluation. Crit Care Med. 2020;48(7):968-976.
11. Hughes JM. Preserving the lifesaving power of antimicrobial agents. JAMA. 2011;305:1027–1028.
12. Carlet J, Jarlier V, Harbarth S, et al. Ready for a world without antibiotics? The Pensières Antibiotic Resistance Call to Action. Antimicrob Resist Infect Control. 2012;1(1):11. Published 2012 Feb 14. doi:10.1186/2047-2994-1-11.
13. ECDC/EMEA Joint Technical Report. The bacterial challenge: time to react. 2009. EMEA/576176/2009. http://www.ema.europa.eu/docs/en_GB/document_library/Report/2009/11/WC500008770.pdf.
14. Alliance for the Prudent Use of Antibiotics: The cost of antibiotic resistance to US families and the health care system. http://www.tufts.edu/med/apua/news/press_release_7-13-10.shtml http://www.tufts.edu/med/apua/consumers/personal_home_5_1451036133.pdf.
15. Roberts R, Hota B, Ahmad I, Scott RD, Foster SD, Abbasi F, Schabowski S, Kampe LM, Ciavarella GG, Supino M, Naples J, Cordell R, Levy SB, Weinstein RA. Hospital and societal costs of antimicrobial-resistant infections in a Chicago teaching hospital: implications for antibiotic stewardship. Clin Infect Dis. 2009;49:1175–1184. doi: 10.1086/605630.
16. De Kracker MEA, Davey PG, Grundmann H. on behalf of the BURDEN group. Mortality and hospital stay associated with resistant Staphylococcus aureus and Escherichia coli bacteremia: estimating the burden of antibiotic resistance in Europe. PLoS Med. 2011;8:e1001104. doi: 10.1371/journal.pmed.1001104.
17. Finkelstein JA, Huang SS, Kleinman K, Rifas-Shiman SL, Stille CJ, Daniel J, Schiff N, Steingard R, Soumerai SB, Ross-Degnan D, Goldmann D, Platt R. Impact of a 16-community trial to promote judicious antibiotic use in Massachusetts. Pediatrics. 2008 Jan;121(1):e15-23. doi: 10.1542/peds.2007-0819. PMID: 18166533.
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27. Okeke IN, Peeling RW, Goossens H, Auckenthaler R, Olmsted SS, de Lavison JF, Zimmer BL, Perkins MD, Nordqvist K. Diagnostics as essential tools for containing antibiotic resistance. Drug Resist Updat. 2011;14:95–106. doi: 10.1016/j.drup.2011.02.002.

Risk of osteoarthritis after an ACL tear and ACL reconstruction

 Risk of osteoarthritis after an ACL tear and ACL reconstruction
                    

                                    Dr. KS Dhillon

Introduction

Osteoarthritis (OA) is the most common type of arthritis. OA is the leading cause of mobility-related disability. Post-traumatic osteoarthritis (PTOA), a subtype of  OA develops after an injury to the joint. The injuries include intra-articular fractures,  ligament injuries, and cartilage (articular or meniscus) injuries. PTOA  accounts for nearly 12% of all arthritis [1].

Unlike idiopathic OA which occurs in older people, PTOA represents a cause of functional disability in a younger population because joint injuries are more often sustained by younger individuals [2]. 

Risk factors for knee PTOA are anterior cruciate ligament (ACL) injury, meniscus tears, patellar dislocation, posterior cruciate ligament tears, and intra-articular fractures.

The incidence of ACL injury is high in adolescents playing sports that involve pivoting. The reported incidence of PTOA following ACL injury is particularly high.

ACL injury and PTOA

ACL rupture is a common and debilitating injury that occurs in athletes who are involved in pivoting sports such as basketball, American football, and soccer. The incidence of ACL tears has been estimated at 0.8 per 1,000 people in the general population. This number is likely to be much higher in younger, more athletic populations [11]. 

Gender is an important risk factor for ACL injuries. Younger women are roughly twice as likely to suffer ACL rupture than young men [4].

About 80,000 to 250,000 ACL ruptures occur annually, and the majority of them in individuals below the age of 30 [5,6,7].

ACL deficiency leads to suboptimal kinematics of the knee since effective transfer of loads relies on mechanical stability. ACL laxity causes deterioration of the physiologic roll-glide mechanism. This results in increased anterior tibial translation as well as increased tibial internal rotation [8]. ACL deficiency results in increased mean contact stress in the posterior parts of the medial and lateral compartments under anterior and rotational loads, respectively [9].

When there is muscle fatigue or poor neuromuscular control, patients with ACL deficiency experience combined anterior and rotatory instability as subluxation of the tibiofemoral joint occurs. In ACL deficient knees the failure of a primary restraint necessitates recruitment of secondary structures such as the menisci to resist external forces and to stabilize the joint. The higher loads borne by secondary structures can make them more susceptible to injury and degeneration [10]. 

ACL injury is usually associated with cartilage injury. Potter et al. [11] prospectively evaluated 40 knees with an acute isolated ACL injury and they found that all patients sustained a chondral injury at the time of ACL tear. They also found that there was an association between the initial size of bone marrow oedema pattern and subsequent degeneration of cartilage [11]. All of these changes may correlate with the eventual development of posttraumatic OA in the knee after an ACL injury. 

About 50% of ACL tears are accompanied by meniscal injury at the time of the acute injury. In the chronic ACL-deficient knee, meniscal tears have been seen in about 80% of the patient population [12,13]. 

Meniscectomy is an important risk factor for developing knee osteoarthritis after an ACL injury. The amount of meniscus resected is the most important surgical predictive factor for the development of OA. 

Lie et al [14] carried out an updated systematic review to assess the prevalence of knee OA at 10 years after an anterior cruciate ligament injury. They found that the prevalence of radiographic knee OA varied from 0% to 100%. They also found that the prevalence of symptomatic knee OA in the tibiofemoral joint was 35% and in the patellofemoral joint 15%.

Øiestad et al [15] carried out a systematic review to study the prevalence of osteoarthritis in the tibiofemoral joint more than 10 years after an anterior cruciate injury. Seven of the studies were prospective and 24 retrospective studies. They found that the prevalence of knee osteoarthritis for subjects with isolated anterior cruciate ligament injury was between 0% and 13% and for subjects with anterior cruciate ligament and additional meniscal injury, the prevalence varied between 21% and 48%. The study also found that the most frequently reported risk factor for the development of knee osteoarthritis was meniscal injury.

After ACL injury, grade III or IV radiologic changes in the knee are nearly 5 times more likely than in contralateral knees without a history of ACL injury. 

There are several risk factors for the development of OA after knee injuries. Meniscectomy is a consistent risk factor for radiographic OA. Meniscus injury often treated by meniscectomy occurs in approximately 75% of patients with ACL injury [14].

The menisci play an important role in providing stability to the tibiofemoral joint. It helps to distribute the load, absorb shock, lubricate the knee joint as well as protect the articular cartilage from excessive axial loading [16]. When the meniscus is damaged the axial loading on the articular cartilage increases and this predisposes and increases the risk of development of OA development [17]. There is a strong correlation between meniscal lesions, cartilage loss, and subchondral bone marrow lesions and these are important factors in the development of OA [18]. Meniscal injuries are common in patients with an acute ACL injury and meniscal injuries can also occur subsequent to ACL injuries. The incidence of OA is higher in patients with combined ACL and meniscus injuries as compared to patients with isolated ACL injuries [14].

Besides meniscectomy, the other risk factors for radiographic OA include gender (female) age, higher body mass index (BMI), obesity, physical activity level, smoking, low education level, subsequent surgery, the time interval between injury and surgery, and varus alignment of the uninjured knee, range of motion loss and articular cartilage damage. 

With older age, there is a disturbance of the balance between anabolic and catabolic processes. There is evidence that suggest that it is related to medial compartment joint space narrowing [19]. It is well known that BMI is associated with the onset and progression of knee OA in patients without ACL rupture. Multiple studies have found that patient BMI is correlated with joint space narrowing and OA following injury to the ACL [20]. Obesity also has a great influence on OA progress in several ways. One is increased joint loading and others include the catabolic effect of inflammatory substances released by adipose tissue, such as free fatty acids, reactive oxygen species cytokines, and adipokines, on joint tissues. 

Physical activity is also considered a risk factor for OA but there appears to be no consensus so far. Physical activity is usually recommended to improve function and promote health. A lack of mechanical loading is also known to contribute to thinning of articular cartilage. A low level of physical activity can lead to an increase in BMI, which is known to lead to the progression of OA.  Repetitive use of joints and joint overload can lead to matrix loss and chondrocyte apoptosis [21].

Some studies have report quadriceps weakness as a risk factor while there are others which state that quadriceps weakness is not a risk factor for radiographic OA [14].

Age has been identified as a risk factor for the development of PTOA. Chondrocyte senescence and preexisting joint degeneration seen in older people increases the possibility of developing OA. 

There have been several studies that have showed that chondral damage is a risk factor for OA [20]. Recurrent episodes of giving way of the knee after an ACL injury can also lead to chondral damage thereby increasing the risks of OA.

Chondral injuries are also known to produce a biochemical cascade, which increases the concentrations of chondrodestructive cytokines and decreases the concentration of chondroprotective cytokines as compared to the contralateral knee [20].

There is some evidence that a time delay between injury and surgery may be a risk factor for tibiofemoral OA. Studies have shown that early reconstruction of the ACL reduces the development of OA when compared with late reconstruction [20].

ACL reconstruction, however, cannot prevent the development of OA and OA can develop regardless of whether a patient undergoes ACL reconstruction or conservative treatment. There is a 57% incidence of knee OA 14 years following ACL reconstruction, as compared to an 18% incidence of knee OA in the contralateral knee [22]. 

A 2014 meta-analysis by Cinque et al [23] showed that the relative risk (RR) of developing radiographic moderate to severe osteoarthritis (grade III or IV) was 3.84. The incidence of moderate to severe OA was 20.3% in ACL-injured knees as compared to 4.9% in the uninjured contralateral knees at an average of 10 years following ACL reconstruction. 

The RR of developing OA in the ACL-injured knees not treated with surgery was significantly higher 4.98 as compared to an RR of 3.62 in knees that were treated with surgery [24]. A more recent meta-analysis showed that the prevalence of radiographic knee OA following ACL reconstruction at 5, 10, and 20 years was  11.3%, 20.6%, and 51.6% respectively [23].

ACL reconstruction does not prevent OA, but ACL reconstruction can delay its onset [25]. 

This is in sharp contrast to other studies that have found no statistical difference in knee osteoarthritis between operative versus nonoperative treatment groups [26,27]. 

A study by Daniel et al [28] concluded that patients who had undergone ACL reconstruction had a higher level of arthrosis by radiograph and bone scan evaluation. Overall, a comparison of bone scan scores for patients who ACL reconstruction as compared to those who did not have surgery revealed a greater incidence of arthrosis in patients who had reconstructed knees.

Risk of arthroplasty after ACL injury

Studies evaluating the risk of knee replacement after ACL injuries is lacking probably because the incidence is very low. Leroux et al (22) did a population-based matched cohort study to evaluate the risk of arthroplasty following ACL reconstruction. They obtained administrative databases of patients who had ACL reconstruction in Ontario, Canada, from 1993 to 2008. They identified 30,301 patients who had ACL reconstruction and 151,362 individuals from the general population with similar demographic variables. They found that 209 patients with ACL reconstruction and 125 patients from the general population had knee arthroplasty. The cumulative incidence of knee arthroplasty following ACL reconstruction after 15 years was low at 1.4% and in the general population, it was 0.2%. Age of 50 years or more, female sex, comorbidity, surgeon annual volume of ACL reconstruction of 12 or less per year, and reconstruction of the ACL done at a university-affiliated hospital, increased the odds of knee arthroplasty. Male sex and an age of 20 years or less were protective indicators. Meniscal tears, however, were not associated with an increased risk of knee arthroplasty.

The limitations of this level 3 study was that it is not known how many of these patients had OA at the time of ACL reconstruction and neither was information about concomitant PCL injury and revision reconstructions available.

Conclusion

Post-traumatic osteoarthritis (PTOA) develops after injury to the joint. The injuries include intra-articular fractures, ligament injuries, and cartilage (articular or meniscus) injuries. PTOA  accounts for nearly 12% of all arthritis.

Unlike idiopathic OA which occurs in older people, PTOA represents a cause of functional disability in a younger population because joint injuries are more often

sustained by younger individuals. 

Risk factors for knee PTOA are anterior cruciate ligament (ACL) injury, meniscus tears, patellar dislocation, posterior cruciate ligament tears, and intra-articular fractures.

ACL injuries are a common cause of PTOA of the knee. The incidence of ACL tears has been estimated at 0.8 per 1,000 people in the general population. About 50% of ACL tears are accompanied by meniscal injury at the time of the acute injury. In the chronic ACL-deficient knee, meniscal tears have been seen in about 80% of the patient population. The incidence of knee OA is higher when there is an ACL tear with a meniscal tear.

The prevalence of radiographic knee OA at 10 years after an anterior cruciate ligament injury varies from 0% to 100%. The prevalence of symptomatic knee OA in the tibiofemoral joint is 35% and in the patellofemoral joint 15%, following an ACL injury.

ACL reconstruction does not prevent OA. Some studies suggest that the incidence of OA is lower after ACL reconstruction as compared to no surgery, others say that the incidence is the same and there is also evidence to show that the incidence is higher after ACL reconstruction.

The cumulative incidence of knee arthroplasty following ACL reconstruction after 15 years is low at 1.4% and in the general population, it is 0.2%. Meniscal tears, however, are not associated with an increased risk of knee arthroplasty.

 

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