Indications for taking blood cultures
\r\n\tThis book will present and discuss the advancement of research on age-associated diseases and their underlying mechanisms, exploring mainly causal relation aspects of the glutathione peroxidase.
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She has graduated from Federal University of Santa Maria / UFSM (Pharmacy - Clinical Analysis, 2006) and she obtained Ph.D. (2010) in Biological Sciences from the same university. She is a member of the research advisory committee (2013), assistant coordinator of research (2014) and academic coordinator (2015) of Campus Chapecó /UFFS. Also she is a leader of the research group: Biological and Clinical Studies in Human Pathologies, professor of postgraduate programs and member of the Committee UFFS Research Advisor. She has experience in the field of Pharmacy, Clinical Analysis, Microbiology, Immunology and Biochemistry, working mainly in the following subjects: oxidative stress, purinergic system and human pathologies. 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Chan and Manoj Kumar Tiwari",coverURL:"https://cdn.intechopen.com/books/images_new/3794.jpg",editedByType:"Edited by",editors:[{id:"252210",title:"Dr.",name:"Felix",surname:"Chan",slug:"felix-chan",fullName:"Felix Chan"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"39628",title:"Blood Culture Systems: From Patient to Result",doi:"10.5772/50139",slug:"blood-culture-systems-from-patient-to-result",body:'Bacteraemia and sepsis is associated with a high mortality and an increased incidence of hospital stay and associated costs [1, 2]. A recent multicentre retrospective evaluation has shown that more than 80% of bacteraemias and fungaemias occur within the hospital or other heathcare settings, with indwelling catheters being the most common source [3].
Blood cultures are still considered to be the ‘gold standard’ for the detection of microbial pathogens related to bacteraemia and sepsis despite newer molecular techniques [4, 5]. This method allows for microbial identification and susceptibility testing to be performed which is a critical component to managing sepsis, however the lack of rapid results and decreased sensitivity for fastidious pathogens has led to the development of improved systems and adjunctive molecular or proteomic testing.
Clinicians need to utilize their respective laboratories’ culturing systems optimally by adhering to the correct way of submitting blood culture specimens, understanding the principle of the testing method and making informed decisions regarding the results obtained.
This chapter will focus on the use of blood culture systems in the era of modern technology and aim to highlight the best practice from collection to interpretation of results.
The term blood culture refers to a single venipuncture, either from a peripheral site or central or arterial line, with blood inoculated into one or more blood culture bottles. One bottle is considered a blood culture where two or more are considered a set. Multiple sets are from multiple venipunctures and are associated with different sites.
Bacteraemia is defined as the presence of microorganisms in the blood, compared to sepsis which is defined as bacteraemia in the presence of clinical symptoms and signs such as fever, tachycardia, tachypnea and hypotension.
The sensitivity and specificity of the test are influenced by the clinicians’ ability to predict bacteraemia or sepsis prior to collection. The clinical indication will guide the timing and the numbers of cultures being send. The person taking the sample will also influence the results by adhering to aseptic technique and inoculating the correct volume.
Blood cultures are taken to establish microbial invasion of the vascular system. Common mechanisms include dissemination from a primary site after inadequate control by host defense mechanisms, intravascular device mediated or infection of the vascular system e.g. infective endocarditis. Transient bacteraemia occur due to translocation of bacteria e.g. during chewing with rapid clearance by immune mechanisms compared to intermittent bacteraemia where bacteria are periodically released into the blood from e.g. an abscess while continuous bacteraemia points to an intravascular infection.
Blood cultures should always be obtained to investigate the possibility of a bacteraemia. Various indications will lead to obtaining these samples (Table 1). Clinical parameters e.g. fever, raised inflammatory markers and suggestive imaging as well as a clinical suspicion of specific disease entities e.g. meningitis, pneumonia, osteomyelitis and pyelonephritis will prompt clinicians to investigate for bacteraemia. Part of the diagnostic criteria for infective endocarditis include obtaining positive blood cultures [6, 7]. Blood cultures are taken to confirm or exclude central line associated bloodstream infection [CLABSI] as well as to follow up the response to therapy in certain conditions e.g. fungaemia and infective endocarditis.
Acute bacterial sepsis | Meningitis |
Pneumonia | |
Osteomyelitis | |
Pyelonephritis | |
Vascular | Infective endocarditis |
Closed space infections | Intra-abdominal abscesses |
Catheter related bacteraemia | |
Follow up cultures | Fungaemia, infective endocarditis |
Indications for taking blood cultures
The yield of blood cultures will depend on the site of infection. Up to 99% of blood cultures can be positive with acute suppurative thrombophlebitis, up to 50% with acute bacterial meningitis and only 2% with acute cellulites.
Collection of blood cultures is a critical component and can either positively affect the patient outcome by providing an accurate diagnosis or adversely affect the outcome by prolonging antimicrobial therapy and the length of hospital stay with the isolation of a contaminant.
In general, clinicians will collect blood cultures around the time of temperature elevation to increase the chance of detecting bacteraemia, however this practice can become complicated especially in patients that are hypothermic or unable to mount a temperature response with clinical sepsis. Fever can also be related to non-infectious causes e.g. drug reaction or malignancy. A multiceneter study showed no significant enhanced detection of bacteraemia when taking cultures around elevated temperatures [8].
The general rule of sending two to three blood culture sets from different sites in a period of 24 hours has also been challenged. For continuous bacteraemia e.g. infective endocarditis the first culture are likely to be positive in contrast to patients with intermittent bacteraemia where 3 or more cultures over a period of time may necessary to detect the pathogen. A study showed no difference in taking cultures simultaneously or serially at spaced intervals [9].
Current recommendation with regard to timing and interval include obtaining two sets within minutes apart from two distinct sites at the onset of the 24 hour period with two subsequent sets being taking at different time intervals over the 24 hour period if the clinical condition deteriorates [10].
Blood cultures taken while on antimicrobial therapy will prevent detection of some bacteraemias, therefore sampling should precede administration of antibiotics at all costs. If patients are on antimicrobial therapy, specific resin containing bottles must be used to neutralize antimicrobials and enhance pathogen detection. Antimicrobial therapy should however never be withheld to obtain subsequent cultures at different intervals.
Key points!
Blood cultures must be taken on suspicion of bacteraemia and not only around fever spikes.
Two sets must be taken at the onset of a 24 hour period within minutes apart.
Two more sets can be obtained during the 24 hour period if the clinical condition deteriorates.
Blood cultures must be obtained before administration of antimicrobial agents.
The recommended practice is to obtain a blood culture from a peripheral venipuncture, however patients who are critically ill and where venous access is a problem will have a central venous catheter (CVC) or an arterial line from which sampling can be performed. This practice has been discouraged due to the concerns of possible contamination [11, 12]. Other studies have shown the benefit of using sampling from CVCs to detect bacteraemia [13, 14]. A recent study by Beutz et al in 2003 evaluated the clinical utility of using blood cultures taken through central venous catheters and peripheral venipunctures in critically ill medical patients and found an overall good negative predictive value, however they warned that in a setting with a high incidence of true bacteraemia the use of taking cultures either through CVCs or peripheral venipunctures should be interpreted with caution, as many critically ill patients who are receiving antimicrobials through their central lines can have negative cultures despite true bacteraemia. They recommend that in patients with a CVC, blood cultures from both the CVC and peripheral venipuncture should be obtained to increase sensitivity but that additional samples may be necessary to trouble shoot discordant results [15]. A recent meta-analysis also showed better sensitivity and negative predictive value with cultures taken from an intravascular site and therefore recommends that at least one culture should be from the CVC [16].
The practice of using the two needle technique, removing the needle after drawing the blood and attaching another sterile needle to inoculate the blood into the bottle, is currently discouraged due to the risk of acquiring needlestick injuries although a meta-analysis showed a slight reduction in contamination rates [17].
Key points!
Peripheral venipuncture is preferred.
If an invasive line is present, do both and correlate.
Keep in mind that the culture from the CVC may be negative if antimicrobials are administered through the line, despite true bacteraemia.
Although the negative predictive value of one culture is good, the sensitivity of taking a culture either peripherally or through a CVC is not adequate.
Blood culture contamination can lead to significant increase in healthcare related costs [12]. Skin antisepsis therefore plays a critical role in reducing these contaminants.
Various antisepsis agents are commercially available and these agents differ by onset of action, mechanism of action and cost. A comparison between povidine – iodine, 70% isopropyl – alcohol, tincture of iodine and povidine – iodine with 70% alcohol detected no significant difference with regard to blood culture contamination rates [18].
Current infection control bundles for insertion of central line catheters and best practice guidelines for taking of blood cultures recommend using 2% chlorhexidine – gluconate in 70% isopropyl – alcohol as skin antisepsis due to the enhanced activity compared to other formulations [19].
In addition to alcohol containing antiseptics, the use of a prepackage antiseptic may play a role in reducing contamination rates [20]. ChloraPrep (Enturia Limited) is a commercial antisepsis system that uses a plastic applicator to release 2% chlorhexidine – gluconate and 70% isopropyl – alcohol into a sponge thereby reducing cross contamination from the care givers’ hands. A study by Tepus et al has shown a reduction in culture contamination rates [21] whereas another showed no significant decrease compared to 70% alcohol impregnated wipes [22].
Key points!
Various skin antisepsis agents are commercially available.
These agents are equally effective in reducing blood culture contamination rates.
The current recommended agent for skin antisepsis when performing venipuncture is 2% chlorhexidine – gluconate in 70% isopropyl – alcohol.
Adequate sample volume remains a critical factor to detect bacteraemia and have been evaluated extensively over last few years. Clinical and Laboratory Standards Institute (CLSI) recommend four 10 ml bottles to detect 90 – 95% of bacteraemias [23]. In order to detect up to 99% of organisms a total of 60 ml of blood will need to be cultured [11].
In the early 1980s Washington proposed that culturing of a higher volume will result in a higher detection rate of blood stream infections [24, 25, 26], however the question arose whether this dictum still holds true for the newer continuous monitoring blood culture systems. Weinstein answered the question by comparing the speed and yield of detection of microorganisms from aerobic bottles inoculated with both 5 ml and 10 ml using a continuous monitoring blood culture system by showing the overall recovery of microorganisms to be higher with the 10 ml inoculated bottles (P < 0.001) [27].
An interesting study found that the higher the age of the patient and the severity of the underlying condition significantly influenced the collection and subsequent culturing of lower volumes of blood. The study also demonstrated that in critically ill patients, the higher the volume cultured, the more bacteraemias were detected and the yield of microorganism recovery increased by 3.5% per additional milliliter of blood cultured [28].
Current recommendations include collecting at least two sets of, each 20 ml of blood distributed equally between an aerobic and an anaerobic bottle from two distinct sites [10, 29]. Lee et al reported that in order to detect 90% of true bacteraemias, 2 blood culture sets should be taken in a 24 hour period, however to detect > 99% up to 4 blood culture sets may be necessary [30].
Single blood cultures should be discouraged due their lack of sensitivity and difficult interpretation e.g. isolating coagulase negative staphylococci (CoNS) from a single blood culture may represent contamination or true bacteraemia [29].
A recent study reported yields from consecutive cultures from patients without infective endocarditis to be 65.1% after the first blood culture, 80.4% after the second blood culture and 95.7% after third blood culture. They also observed a high positivity from the first culture in patients with infective endocarditis which supports the observation of a continuous bacteraemia and fungaemia in this patient group [10].
Although paediatric bottles have been adapted to accommodate much smaller volumes of blood the optimal amount remains unknown. It is common practice to culture not more than 1 – 2 ml of blood in neonates. One study suggests that failure to detect bacteraemia was more likely when culturing < 1 ml of blood [31].
Human blood contains various factors or substances that can interfere with the detection of micro-organisms e.g. host serum factors and also antimicrobial agents. Therefore inoculated blood must be diluted to a point where these substances will have a minimal inhibitory effect. The required dilutional factor has been evaluated before and up to 10 times dilution has been recommended [32, 33], however the blood – broth ratio required for various systems will differ according to manufactures’ instruction. The VersaTREK (TREK Diagnostic Systems, Cleveland, Ohio) is adapted to accommodate smaller volumes from as little as 0.1 ml – 10 ml, however the manufacture still recommends using 10 ml to achieve a 1:9 blood – broth ratio in the 80 ml bottle. Inoculating at dilutions higher than 1:10 may be associated with a lower yield due to the decreased overall volume cultured [29].
Key points!
The higher the volume, the higher the yield.
Up to 4 blood culture sets in a 24 hour period may be necessary to detect > 99% of microorganisms.
As least 1 ml must be cultured in neonates.
Adequate blood – broth ratio of 1:10 must be achieved to dilute the effects of inhibitory substances and antimicrobials present in the blood.
Education and training of staff responsible for collection of blood cultures is critical. Studies have shown a decrease in contamination rates associated with combining different measures with training [34, 35] with the one study reporting contamination rates from phlebotomist vs. non-phlebotomists to be 0.8% and 4.7% respectively [35].
Key points!
Lower contamination rates are possible with dedicated phlebotomists.
Although all positive blood cultures are regarded as significant, false positive results can occur and interpretation becomes critical. Clinical information can aid the laboratory to decide whether an isolate is more likely to be significant or a contaminant [See section on Blood culture contamination].
Labeling of each bottle especially indicating the site through which the sample was taken is of critical importance to the laboratory. Sets taken through catheter lines are more likely to be contaminated and therefore correct labeling can aid interpretation.
Avoid applying the label over the barcode or the bottom of the bottle, this practice cover the sensor that is critical for detection and can result in false positive signals.
Key points!
Label bottle with the site where the sample was obtained from.
Covering the sensor at the bottom of the bottle can result in false positive signals.
This new strategy to decrease blood culture contamination has been implemented in some centers. The kit contains a pre-packaged antiseptic e.g. ChloraPrep sponge, a blood collection set [needle, syringe, safety lock etc], bottles and an instruction leaflet. A study evaluating the impact of these blood culture collection kits showed a reduction in blood culture contamination rates from 9.2% – 3.8%, however introduction of the kit was associated with an unintended yet sustained decrease in the amount of blood cultures collected which may have resulted in an unwanted reduction in the amount of true Gram negative bacteraemias [34]. The authors recommend using the kit with ongoing training and ensuring that availability and accessibility are not compromised. Weightman et al also reported a decrease in contamination rates observed at their centre after the introduction of blood culture collection kits from 6% - 2.7% without compromising the amount of investigations performed [35].
Key points!
Blood culture collection kits can decrease blood culture contamination rates.
Blood culture sets generally consist of and aerobic an anaerobic bottle. Various different bottles are available depending on the continuous monitoring system used. These bottles are specifically designed to optimize recovery of both aerobic and anaerobic organisms. This section will highlight the principles of these bottles by discussing a few examples, more detail with regard to specific bottles not mentioned should be obtained from the manufacturer.
Despite a decrease in the amount of anaerobic organisms isolated, the use of the anaerobic bottle as part of the routine blood culture set continuous. Various authors have questioned this practice [36, 37]. Morris et al suggested that an approach of using two aerobic bottles with selective anaerobic culturing could enhance isolation with up to 6% [36], however this approach has not been adapted. Tamayose et al argued strongly to discontinue anaerobic culturing as routine practice and place attention on enhancing fungal isolation. [37]. The anaerobic bottle however adds value in the fact that it allows growth of facultative organisms and thus adding to the total volume cultured and thus the sensitivity for organism recovery.
Various culturing media within one system differ with regard to constituents and performance and the choice relies heavily on controlled clinical evaluation. The BacT/ALERT FN medium (bioMérieux, Durham, N.C.) recently replaced the BacT/Alert anerobic FAN medium. They differ in composition with the amount of activated charcoal and broth constituents where the FN bottle contains a higher concentration of activated charcoal as well as trypticase soy broth compared to brain heart infusion. BacT/ALERT also has a standard anaerobic bottle SN which does not contain activated charcoal. Mirret el al compared all three anaerobic bottles with the standard aerobic bottle, the BacT/ALERT FA medium and found better recovery of micro-organisms and a faster time to positivity [TTP] with the FN bottle [38].
Often the culturing media may differ in the structural format e.g. the BacT/ALERT 3D system (bioMérieux, Durham, N.C.) uses plastic bottles compared to the Bactec9240 system [BD Microbiology, Cockeysville,MD] that uses glass bottles. The VersaTREK system (Trek Diagnostic Systems, Cleveland, OH) offers media in two forms for both aerobic and anaerobic isolation, the 40 ml direct draw format which can accommodate 5 ml and an 80 ml format which can accommodate 10 ml. With the direct draw format the blood – broth ratio achieved is 1:8. Samuel et al compared the two media types with simulated blood cultures with clinically relevant microorganisms and found no negative impact on TTP with the smaller volume bottles [39]. Caution should be applied in not compromising the total volume cultured when using small volume bottles as the recommended volume to be cultured still remains 30 ml of blood (See section on Principles of blood culture collection).
Some blood culture bottles contain the anticoagulant sodium polyanetholsulphonate (SPS) that can inactivate some of the host serum factors but also have a toxic effect on some organisms. An overall balance is achieved with the correct blood – broth ratio. The blood – broth ratio required and achieved will be different between systems [See section on Principles of blood culture collection]. Bottles also differ in terms of the antibiotic binding resins used to limit the effect of inhibitory substances. A study compared the Bactec Plus media and TREK Redox media and found the former to be more efficient in recovering organisms in the presence of antimicrobial substances [40].
Paediatric bottles are specifically adapted to accommodate smaller volumes and often contain additional growth factors and binding resins to enhance organism recovery. A common misconception is that standard bottles cannot be used on paediatric patients and vice versa, however the choice of bottle will be dictated by the volume obtained. Although paediatric bottles are designed to maximize growth from smaller volumes the sensitivity to detect bacteraemia will increase with the volume of blood cultured. In neonates and infants it is assumed that you sample a much smaller pool and therefore the volume necessary to detect bacteraemia must be smaller, however as highlighted before the total volume required is not known and due to restriction in obtaining high volumes from this patient population this answer will keep eluding us. One study however has shown that the chance to fail to detect bacteraemia will increase when culturing < 1 ml in neonates [31].
Some systems provide additional culturing media optimized to detect fungal or mycobacterial pathogens more efficiently, however these will not be addressed in this chapter.
Over the years blood cultures has been regarded as one of the most import specimen types and microbiology laboratories take great care to process these as rapidly as possible. Blood cultures that have been collected must reach the laboratory as soon as possible and generally receive high attention for immediate incubation to allow optimal growth of organisms and rapid recovery without compromising the specimen.
Although in principle, the bottles must be inserted within the continuous monitoring blood culture systems as soon as possible, various factors can affect the time to insertion [TTI]. Some laboratories do not operate a full 24 hours and bottles will then be incubated at 35⁰C and can only be inserted the following day. Other factors include a delay in reaching the laboratory due to logistics. A study by Saito et al evaluated the effect of delayed insertion of blood culture bottles into continuously monitoring blood culture systems and found that although delayed insertion did not affect the sensitivity for organism recovery the mean TTP for all isolates was significantly shorter if inserted on the same day that the culture was obtained [41].
Time to removal (TTR) is defined as the time elapsed from when the system emits a positive signal until the bottle is removed for subsequent subculturing for organism recovery. A delay in removal of the bottles could be due to closure of the laboratory at night and this can result in obtaining false negative results especially when isolating more fastidious organisms. In our study when evaluating the VersaTREK system against the Bactec9240 system we found that the time to removal (TTR) for some isolates were up to 8 hours and this could have explained some false negative results where the system failed to detect S. pneumonia isolates [42]. We know that this organism is prone to activate autolysin under stress conditions which may result in poor recovery from blood culture bottles. This phenomena has been observed with the BacT/ALERT 3D system in our laboratory where positive signals were obtained with subsequent no growth, however confirmed after positive agglutination from the bottle sediment (data not shown).
The duration of incubation is calculated from the time of insertion until the time of removal. Bottles will be removed, thus considered negative, when no positive signal is obtained after a certain amount of incubation time has elapsed. This time before removal will depend on the blood culture system used. For manual broth – based systems, 7 days are the recommended incubation time [43] in comparison to various studies that support shorter incubation times of 4 to 5 days with the continuous monitoring blood culture systems [44,45,46].
Extended incubation (up to 14 to 21 days) is still recommended to detect more fastidious organisms specifically the HACEK organisms (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella species) that are involved in endocarditis [7]. Recent reports have shown that the method of detection and not the time of incubation is critical to detect these organisms. Baron et al in 2005 reported evidence that the Bactec9240 system can detect the HACEK organisms within 5 days [47]. Alternative methods e.g. a lysis centrifugation system for dimorphic fungi and molecular methods for Bartonella\n\t\t\t\thenselae may be of more value than prolonged incubation [47, 48]. In a multicentre evaluation of 15 826 positive blood cultures only 0.1% of HACEK organisms were detected across all centers with a mean time to detection of 3.4 days. They recommend based on their findings that extended incubation for HACEK organisms is unnecessary [49].
Various commercial blood culture systems are available. The choice of blood culture system will depend on various factors (Table 2). It is the responsibility of the laboratory director to liaise with clinicians on the selection of the best system to achieve the best results for their specific patient population and workload.
The various blood culture systems compete with regard to sensitivity for organism recovery, TTP, workload capacity, user interface and associated costs. Not one system is perfect and able to detect all possible micro-organisms.
These systems all require inoculation of blood into a media bottle. The media are in principle similar, however controlled clinical trials have shown some media to be superior for certain organisms [See section Selection of the correct blood culture bottle].
Sensitivity for organism recovery is the most import parameter when selecting a blood culture system. Studies have shown that the lysis centrifugation systems are more sensitive for the detection of fastidious organisms and dimorphic fungi [25]. The continuous monitoring systems have shown superiority with regard to TTP compared to manual systems [50, 51, 52, 53] and are the current preferred systems. TTP has been shown to be a good predictor of clinical outcome in staphylococcal sepsis [54, 55, 56].
Sensitivity for organism recovery |
Time to positivity |
Workload capacity |
User interface |
Costs |
Factors that affect the choice of blood culture system
The workload capacity is important as many laboratories differ in the amount of blood culture they will process. The continuous monitoring systems have the capacity to be expanded to accommodate the workload. The interface must be user friendly e.g. some technologists will review the growth index of the bottle to troubleshoot possible false positive signals. Cost of implementation and maintenance may play a role as well.
There are currently a wide variety of blood culture systems available. Although the continuous monitoring blood culture systems have become the preferred platform, manual systems are still available and used in some settings and will be discussed briefly.
The conventional manual method entails inoculating a commercially provided blood culture bottle, incubating the bottle at the required temperature and atmosphere with daily inspection of the bottle for macroscopic evidence of growth e.g. turbidity, haemolysis or colonies. Once growth is observed, a sample can be obtained for Gram staining and subculture for further identification. Bottles are incubated for 7 days and terminal subculture is mandatory.
Variations to the conventional manual method is combining agar in the form of paddles to the broth. These systems allow for more frequent subculturing by inverting the bottles to bring the broth into contact with the agar. These bottles can be inspected for growth and Gram staining with presumptive identification to be performed from the agar.
The Septi-Chek (BD Diagnostics) blood culture system is a biphasic-agar slide system that uses a standard blood culture bottle containing brain heart infusion or trypticase soy broth connected to a second plastic chamber with a trisurface panel consisting of chocolate, Mackonkey and malt agar. The slide chamber is screwed onto the bottle after inoculation and incubated at 35°C for 4 – 6 hours. The bottle is then inverted for the first subculture and can be inverted at various intervals thereafter to optimize isolation.
The Oxoid Signal System (Oxoid Unipath, Basingstoke,England) is unique in the sense that it is a one bottle system. After inoculation of a standard blood culture bottle a second chamber is attached with a long needle that extends below the surface of the blood – broth mixture. This closed space system uses CO2 production to detect growth. Any gas produced will increase the pressure in the headspace and allow some of the blood – broth mixture to enter into the chamber from where sampling, Gram staining and subculturing can be performed. This system thus signals the laboratory towards possible growth without using an automated system. The advantages and disadvantages of these systems are presented in Table 3.
Advantages | Disadvantages |
Evaluated favourably in detecting growth | More false positives |
Cost effective | Lower yield of anaerobes |
Useful in small laboratories with small workload | Labour intensive, need to visibly inspect for growth |
Advantages and disadvantages of manual blood culture systems
The principle of this test is explained in its name. The Wampole Isostat/ Isolater Microbial System (Inverness Medical) is a single tube test that uses saponin for lyses of erythrocytes and neutrophils, followed by centrifugation and subsequent inoculation of solid agar media for isolation. The system is useful for the recovery of slow growing and fastidious organisms including filamentous moulds, dimorphic fungi and Bartonella\n\t\t\t\t\t\thenselae [29]. This method also allows quantification to be performed, however limitations include a higher rate of contamination, excessive hands on time and toxic effects of the saponin that can inhibit growth.
These systems are considered an advance in clinical microbiology and are the current preferred platform for blood culture testing worldwide. With the introduction of these systems in the 1970s they have evolved over time e.g. the Bactec series started with radiometric systems which was later replaced with non – radiometric systems. Today we face automated and computerized continuous monitoring blood culture systems.
The three main commercially available systems are the BacT/ALERT blood culture system (bioMérieux, Durham, N.C), Bactec 9000 series (BD Microbiology, Cockeysville,MD) and the VersaTREK system (Trek Diagnostic Systems, Cleveland, Ohio). All three systems have expandable detection units with self-contained incubation chambers and minimal bottle manipulation as agitation is achieved via rocking or vortexing. The principle of detection of these systems is based on the release of CO2 in the presence of micro-organism metabolism.
The Bact/ALERT and Bactec systems both depend on a pH change due to the production of CO2 to detect growth. The Bactec9240 systems’ bottles have a sensor at the bottom that emits a fluorescent light as the CO2 concentration increases, that will pass via an emission filter to a light sensitive diode. The system measures the voltage every 10 minutes and compares the new value with the previous value and emits a positive signal as soon as the threshold value is reached. The BacT/ALERT 3D system uses a CO2 sensitive chemical sensor that is separated from the blood – broth mixture via a unidirectional membrane. Once the CO2 concentration increases, the colour will change from green to yellow, this is measured with a photosensitive detector.
The VersaTREK system monitors changes in the bottle headspace every 24 minutes. Both gas consumption and production are monitored. As a result other gasses e.g. O2 and H2 are also detected. The system differs from the other systems in that the aerobic bottles are vortexed with a magnetic stir bar to increase oxygenation.
All three systems have been compared for both sensitivity for organism recovery and TTP. Mirret et al compared the VersaTREK system with the BacT/Alert system and found no significant difference for the detection of bacteraemia or fungaemia in clinical isolates [57]. Our group compared the VersaTREK system against the Bactec9240 system and found both systems comparable to detect bacteraemia in patients with suspected sepsis however we observed a higher rate of false positive results and postulated that the threshold setting to emit a positive signal might be too low [42]. Comparison of the BacT/ALERT system with the Bactec9240 systems showed slight better detection with the former [58]. Advantages and disadvantages of these systems are shown in table 4.
Advantages | Disadvantages |
Higher sensitivity for organism recovery | High implementation cost |
Faster TTP | Equipment must be maintained |
Fully automated and computerized | Need continuous power supply |
Easy loading and unloading of bottles | |
Expandable to accommodate larger or smaller volumes |
Advantages and disadvantages of continuous monitoring systems
Time to positivity (TTP) is a parameter provided by the automated blood culture system and is calculated from the time of incubation until a positive signal is detected. TTP can be influenced by various factors e.g. the bacterial load, the growth rate of the micro-organism, the presence of antibacterial substances in the blood as well as source of infection and clinical features.
Differential TTP has been used to diagnose CLABSI [59, 60, 61]. Two sets of blood cultures are taken at the same time, one through the inserted catheter and the other peripherally. A CLABSI should be suspected if both sets yield the same micro-organisms and the set taken through the line becomes positive (TTP) 120 minutes or earlier than the peripheral set [62].
Short TTP in S. aureus bacteraemia can possibly predict the source of infection, specifically an endovascular source and also correlate with the attributable mortality [54].
Combining the TTP with the initial Gram stain result could predict the micro-organism as well as the source of bacteraemia, e.g. patients not on antimicrobial agents with Gram positive cocci in cluster within 14 hours was predictive of S. aureus, however the clinical impact of using this approach needs to be evaluated further [63].
Interpretation of positive blood culture results are challenging to both clinicians and microbiologists. With the background of blood culture contamination rates of up to half of all positive cultures and previously considered contaminants now more frequently implicated in disease the need for tools to assist in distinguishing contaminants from pathogens becomes eminent.
Consensus have been reached with regard to clinical and laboratory parameters that must be taken into consideration to assess positive cultures for significance or contamination. These include fever, leucocytosis, positive imaging, the identity of the organism recovered, the number of sets positive out of the number received, the number of bottles positive within a given set and the TTP [64] (Table 5).
Clinical | Laboratory |
Fever | Identity of the microorganism |
Leucocytosis | Number of positive sets |
Positive imaging | Number of positive bottles (within set) |
Time to positivity |
Parameters as tools to distinguish contaminants from pathogens in positive blood cultures
The identity of the microorganism can aid interpretation of results [11, 65]. According to an evaluation by Weinstein et al in 1997 there are organisms that will be pathogens in > 90% of cases and these include Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, other Enterobacteriaceae, Pseudomonas aeruginosa and Candida albicans [66]. Despite adequate data from large studies there are other organisms that also presents as true pathogens most of the time e.g. Streptococcus pyogenes, Streptococcus agalactiae, Listeria monocytogenes, Neisseria meningitidis, Neisseria gonorrhoeae, Haemophilus influenzae, Bacteroides\n\t\t\t\tfragilis group, Candida species other than C. albicans and Cryptococcus neoformans [64]. Organisms that represent rarely as pathogens include Bacillus species, Propionibacterium acnes, Corynebacterium spp other than C. jeikieum and Viridans group streptococci [66, 67] (Table 6).
True pathogen | Probable contaminant |
Staphylococcus aureus | Coagulase negative staphylococci (CoNS)* |
Streptococcus pneumoniae | Bacillis species |
Escherichia coli | Propionibacterium acnes |
Other Enterobacteriaceae | Corynebacterium spp |
Pseudomonas aeruginosa | |
Candida albicans |
Organism identity to indicate significance or contamination
Other organisms can no longer be judged on their identity with regard to significance, these include CoNS, Viridans group streptococci and Clostridium species.
Isolating CoNS from positive blood culture bottles presents a challenge for clinicians in deciding the significance of the finding. Not only are CoNS the most common contaminant isolated but patients who presents with true infection often have mild symptoms which makes the interpretation very difficult [68,69]. Various studies are reporting CoNS to be a true pathogen causing blood stream infections especially in patients with indwelling prosthetic devices or central venous catheters [66, 70].
The value of obtaining more than one set of blood cultures not only enhances the yield of detecting bacteraemia, but also aids interpretation when dealing with positive cultures. Contaminants are often obtained from only one set whereas with true bacteraemias multiple blood cultures will grow the same organism [66]. Weinstein also reported that if an institution has a baseline contamination rate of about 3%, the chances of recovering the same organism in a two set culture and being a contaminant is less than 1 in a 1000 [64].
Using the TTP as an aid to establish significance have been debated before [64]. The principle relies on the assumption that true infection will present with a much larger inoculum vs. contamination and thus result in earlier detection. One of the reasons why TTP can be misleading is the fact that continuous monitoring systems can detect micro-organisms at lower levels much faster than conventional systems.
Using the criteria that if one bottle is positive within a given set relates to contamination should be discouraged. For CoNS this has been evaluated and shown to be inadequate to predict clinical outcome [71].
Culture contamination represents false positive results and are not uncommon in microbiology laboratories with rates being reported as high as around 50% of all positive cultures [66, 72]. An increase in contamination rates despite advances in the field of microbiology has been observed [66] and this phenomenon could be explained by the increasing use of continuously monitoring blood culture systems and the improved culture media provided for the specific systems that may aid the detection of low numbers contaminants. The increased use of intravascular devices and the practice of taking cultures through invasive lines are also important when considering contamination rates. American Society of Microbiologists published standards that state that blood culture contamination rates must not exceed 3% [73], rates however will differ widely between institutions, but commonly exceeds 7% [74, 75].
The cost of blood culture contamination often exceeds the cost of performing the test [76]. A retrospective case-control study evaluated 142 false positive blood cultures and found a significant increase in length of hospital stay as well as laboratory and pharmacy costs, they also calculated that the 254 false positives blood cultures in a year period, added 1372 extra hospital days and £1,270,381 in costs per year [77].
Various strategies have been implemented to decrease blood culture contamination rates e.g. training staff with regard to aseptic collection technique, feedback with regard to contamination rates and implementation of blood culture collection kits. Although skin antisepsis can reduce the burden of contamination, 20% of skin organisms are located deep within the dermis and are unaffected by antisepsis [78]. The practice of changing needles before bottle inoculation should be abandoned as it increases the risk to acquire needle stick injuries without decreasing contamination rates [79]. Also discarding the initial aliquot of blood taken from CVCs does not reduce contamination [80].
In hospital settings where resistance profiles of circulating micro-organisms are known, the use of rapid identifying methods to guide empiric antimicrobial usage is critical to improve patient outcomes. Research efforts are focused on developing molecular tests that can be performed without prior culturing with continuous monitoring systems, however these assays are limited to date. Molecular assays performed on positive blood culture bottles has improved sensitivity compared to conventional culturing methods, and has decreased turnaround times compared to routine culture [81]. Study by Karahan have shown the use of molecular methods to evaluate false positive signals for identifying microbial DNA of organisms that might have been inhibited by high leucocytes count or antimicrobials [82].
The Lightcycler® SeptiFast (Roche Diagnostics, Manheim, Germany) is a multiplex realtime PCR system that can detect up to 25 common pathogens involved in sepsis from one single blood sample within 6 hours. Various studies have evaluated the use and confirm increased detection of circulating microbial DNA compared with conventional blood culture [83, 84,85]. Study by Lucignano et al evaluated the use in the paediatric population with suspected sepsis with sensitivity and specificity reported of 85% and 95% respectively. Significantly higher yields were observed from patients already on antimicrobial therapy [86]. Although this method is considered culture – independent, most studies agree that this system does not replace conventional blood culturing and the clinical significance of detecting higher amounts of microbial DNA must be further evaluated.
A new strategy for the detection of blood stream pathogens include PCR/Electrospray ionization and mass spectrometry [PCR/ESI-MS]. This technique in short amplifies broadly conserved regions of bacterial and fungal genomes followed by mass spectrometric analysis by weighing the PCR amplicons and comparing the product with known standards. The commercial assay is the Bac Spectrum Assay that runs on the PLEX-ID (Abbott Molecular). A study by Eshoo et al showed good sensitivity and specificity for the detection of Erlichia species in the blood from patients with suspected erlichiosis with the identification of additional bacterial pathogens that was determined to be clinically relevant [89]. This new method will likely change the future of diagnosis of bloodstream pathogens however clinical relevant studies needs to be performed.
The Prove-it sepsis assay (Mobidiag, Helsinki, Finland) is a DNA-based microarray platform can identify more than 50 Gram positive and Gram negative bacteria that can cause sepsis [87] as well as detect the presence of the mecA gene that codes for methicillin resistance in S. aureus [88] from positive blood culture bottles. Sensitivity and specificity compared to conventional culture are reported to be 94.7% and 98.8% respectively [81]. The study also showed an 18 hour faster turnaround time for identification compared to conventional culture. Due to the multiplexing capabilities this assay can also be expanded to detect pathogens involved in fungaemia.
The Xpert MRSA/SA Blood culture assay [Cepheid] was evaluated favourably for the detection of an the discrimination between methicillin resistant staphylococcus aureus (MRSA) and methicillin susceptible staphylococcus aureus (MSSA) [90]. Although this method is limited with regard to the range of pathogens it will guide initial empiric therapy towards a better clinical outcome.
Another new approach to enhance earlier specie identification from positive blood culture bottles following Gram staining include the Peptide Nucleic Acid Fluorescence In situ Hybridization assay (PNA-FISH). This assay uses probes that target specific conserved bacterial and fungal genomic regions and can distinguish between e.g. S. aureus and non – S. aureus as well as different Candida species [91, 92, 93].
Matrix-assisted Laser Desorption/Ionization–time of flight (MALDI-TOF) mass spectrometry [MS] is currently widely applied on post culture isolates for rapid identification. The system use MS signals created and compare them to standard signal patterns within a database. The use directly from positive blood culture bottles needs further evaluation but the advantage of this technology shows promise for the future.
The various new technologies appears attractive, however implementation will come at great cost and are not cost effective for routine laboratories at present. Certainly the rapidly of results being generated and the ability to detect pathogens unlikely to grew on conventional media comes as a great advantage. The clinical significance of enhanced detection of circulating microbial DNA must be established.
The use of blood culture systems still remain the gold standard for the detection of bacteraemia. It is important to understand the process from collection to obtaining a result to aid interpretation and improve the clinical outcome. While the continuous monitoring systems are the preferred platform for testing, various new methods are on the horizon that will aid or even replace these systems, only time will tell.
Rotator cuff tears affect millions worldwide; given their age-dependent increase in prevalence, they pose a significant healthcare burden on today’s aging population [1]. Chronic large to massive rotator cuff tears are often considered “irreparable” secondary to poor tissue quality, tendon retraction, and muscle atrophy and fatty infiltration [2]. Surgical options for treatment of these tears have not demonstrated consistently good outcomes [2, 3, 4]. These include attempts at relieving pain by way of debridement with or without biceps tenotomy; balancing the anterior/posterior force couples by way of partial repair; restoring cuff integrity by way of interpositional grafting; and tendon transfers. Reverse shoulder arthroplasty has been gaining popularity and demonstrates good outcomes as a treatment option for patients with rotator cuff arthropathy, but is typically reserved for the elderly patients. Massive and irreparable rotator cuff tears in younger and more active individuals, especially without significant arthritic changes of the glenohumeral joint, remain a clinical conundrum.
Recently, a new surgical procedure called superior capsular reconstruction (SCR) was described by Mihata et al., who reported promising short-term clinical outcomes in 24 shoulders (23 consecutive patients) with symptomatic irreparable rotator cuff tears [2]. Although the procedure has a strong appeal for physicians treating patients with this difficult problem and has been quickly gaining popularity, caution regarding widespread use is warranted, as large-scale and long-term data is still lacking. This chapter reviews the anatomy and function of the rotator cuff and shoulder capsule; patho-etiology of rotator cuff tears; and rationale, techniques, outcomes, and future direction of superior capsule reconstruction for irreparable tears.
The rotator cuff is composed of the musculotendinous units that bound the glenohumeral joint. Its components are supraspinatus (SS), infraspinatus (IS), teres minor (TM), and subscapularis (SSC) muscles [5, 6] (Figure 1). The supraspinatus, which is most commonly involved in rotator cuff tears, originates on the superior aspect of the scapular body, in the supraspinous fossa, and inserts onto the anterior-superior aspect of the greater tuberosity of the humerus. The infraspinatus originates on the posterior scapular body, from the infraspinous fossa, and inserts on the posterior-superior aspect of the greater tuberosity. The teres minor, which is rarely involved in rotator cuff tears, originates from the lateral lower-half of the scapular body, inferior to the infraspinatus, and inserts on the posterior – inferior aspect of the great tuberosity and humeral head. The subscapularis, which is the largest muscle of the rotator cuff group, originates from the anterior scapular body (the subscapular fossa), runs deep to the coracoid process, and inserts onto the lesser tuberosity of the humerus. Innervation to the rotator cuff comes from the C5-6 nerve roots, with the suprascapular nerve supplying the supraspinatus and infraspinatus, axillary nerve supplying teres minor, and the upper and lower subscapular nerves supplying the subscapularis. The close interplay and confluence of the different parts of the rotator cuff creates several structures important for glenohumeral joint stability and function. These include the rotator interval, crescent, and cable.
Arthroscopic views of the rotator cuff tendons (left shoulder). (A) Intraarticular view from the posterior portal, showing the humeral head (HH), supraspinatus (SS), subscapularis (SSC), the long-head of the biceps tendon (LHBT), the middle glenohumeral ligament (MGHL), and rotator interval (RI). (B) Bursal view of the superior rotator cuff (SS and IS)..
The rotator interval (Figure 1A) is the anterior triangular space between the anterior border of the supraspinatus and superior border of the subscapularis, and contains the anterior glenohumeral joint capsule, the coracohumeral ligament (CHL), and the superior glenohumeral ligament (SGHL). The interval helps maintain the biceps tendon within the bicipital groove, and also contributes to stability of the glenohumeral joint [7, 8]. The rotator interval is also often implicated in the adhesions and contractures that occur in adhesive capsulitis of the shoulder.
The rotator crescent is a thin sheet of rotator cuff tendon, comprising the distal portions of the SS and IS insertions. The crescent is proximally bound by a thick bundle of fibers—the rotator cable—that runs perpendicular to the SS and IS fibers. Burkhart et al. described a biomechanical model of rotator cuff tears using 20 cadaver shoulders, where the rotator cable acts as a stress shield for the crescent, and the two structures form a “suspension bridge.” According to this model, tears in the crescent have minimal effects on shoulder function, while those that involve the cable impair its ability to distribute the load and tension between the anterior and posterior rotator cuff and therefore its role as a dynamic stabilizer of the humeral head [9]. This concept has clinical implications as it helps guide decision making in identifying tears that can be managed non-operatively, versus those that require surgical fixation.
While the rotator cuff is the main dynamic stabilizer of the glenohumeral joint, the glenohumeral joint capsule acts as a static stabilizer. It is a thin membranous structure located deep to the rotator cuff; it originates medially from the glenoid neck and inserts laterally to the anatomical neck of humerus.
The capsule is thicker anteriorly than posteriorly. The anterior capsule contains focal thickened bundles, which are called superior, middle, and anterior-inferior glenohumeral ligaments (GHL). The posterior capsule has an inferior thickening called the posterior-inferior GHL, but does not have separate ligaments further superiorly. Directly inferiorly, between the anterior-inferior and posterior-inferior glenohumeral ligaments, the capsule forms the axillary pouch, which tightens in abduction, and relaxes in adduction [3, 4, 5, 10]. Contracture and loss of normal axillary pouch volume is frequently seen in adhesive capsulitis, whereas a patulous capsule with an enlarged pouch is often seen in multi-directional shoulder instability.
The superior capsule is thin and was previously less well-studied. It originates from the glenoid neck along with its anterior-posterior counterparts, courses directly underneath the SS and anterior part of the IS, and attaches to 30–61% of surface area of the greater tuberosity (GT) [5, 10]. Nimura et al. measured superior capsule attachments in cadaveric shoulders. They reported thicker footprint at the anterior edge of SS and posterior edge of IS (5.6 ± 1.6 mm and 9.1 ± 1.7 mm, respectively), whereas the attachment was thinner at the middle area of the rotator cuff, near the posterior margin of SS (4.4 ± 1.2 mm). The authors concluded that the thinnest point of the capsule could contribute to the etiology of the initiation of degenerative rotator cuff tears [5]. The superior capsule is closely associated with the SS and IS, and typically tears together with complete tears of these tendons [1, 2, 3, 4].
The muscles of the rotator cuff help initiate movement of the shoulder joint, and also serve as the main dynamic stabilizer of this joint. Supraspinatus aids in abduction of the humerus, particularly in the scapular plane; external rotation is provided by infraspinatus (more active in adduction), and teres minor (more active in abduction); and internal rotation is the function of subscapularis. Furthermore, SS prevents abnormal inferior-superior translation of the humeral head, particularly during active arm elevation, by compressing the head into the glenoid fossa. The balancing forces between SSC anteriorly and IS and TM posteriorly provide stability in the sagittal plane, and the upward force of the deltoid is balanced by that of IS, TM, and SSC in the coronal plane [11, 12].
The shoulder capsule provides static stability, serving to prevent excessive translation of the humeral head relative to the glenoid [5, 10]. The anterior capsule prevents anterior translation, while the posterior prevents posterior translation. The function of the superior capsule was previously poorly understood and continues to be studied. Ishihara et al. demonstrated in a biomechanical study that the superior capsule plays an important role in passive stability in all directions, and cutting it significantly increases abnormal translation, especially superiorly [10]. This can lead to a decrease in the acromiohumeral distance—a finding commonly seen in patients with chronic massive superior cuff tears as well as cuff-tear arthropathy [2] (Figure 2).
Anterior-posterior plain radiograph of a left shoulder with rotator cuff arthropathy. Note the “high-riding” humeral head, with a decreased acromiohumeral distance, and interrupted Shenton’s line at the inferior aspect of the glenohumeral joint.
While a significant number of rotator cuff tear cases present to the physician after a traumatic episode, most tears do not occur in a setting of a normal tendon. Preexisting degenerative changes are usually found in the torn tendons, and the injury that leads to clinical presentation is likely the “straw that breaks the camel’s back.” A number of both intrinsic and extrinsic pathways and risk factors are thought to contribute to chronic degeneration and weakening of the cuff tendons, as described below (Table 1).
Strong association | Controversial or weak association |
---|---|
Age (particularly >60) Smoking (dose and time-dependent) Family history Previous history of tear Trauma Hypercholesterolemia Heavy labor and overhead athletes (chronic wear-and-tear) | Peripartum Hormonal changes Dominant side Postural abnormalities |
Risk factors for rotator cuff pathology.
The main intrinsic mechanism pathway is thought to be tenocyte apoptosis and inflammation resulting from chronic microtrauma to the rotator cuff tendons. Advancing age is the most common reason for this mechanism, and age has been found to be the strongest risk factor for rotator cuff disease. This is thought to be due to the combination of age-related degenerative changes and accumulation of microtrauma and macrotrauma over the course of an individual’s lifetime [3, 4]. Older patients are also more likely to develop larger tears; Gumina et al. reported a mean age of 59 years in a group of 586 patients undergoing arthroscopic tear repair, with those older than 60 being twice as likely to develop large and massive tears [13].
Tendon degeneration and poor healing potential are exacerbated by hypovascularity, which is worsened not only with advancing age, but also with smoking, and certain other conditions [4]. Smoking has a strong dose and time-dependent association with both the prevalence and size of tears; it negatively affects the vascularity of tendons, thereby predisposing them to tears and preventing healing [3, 4]. Similarly, hypercholesterolemia has been implicated in rotator cuff disease. The mechanism here is thought to be deposition of cholesterol by-products within the rotator cuff tendons, leading to worsening of biomechanical properties of the tendon and increasing the risk of tearing [14].
Genetic predisposition may also play a role. Patients diagnosed relatively early in life (before age 40) often have a family history of rotator cuff disease [3]. Particularly in irreparable tears, studies have shown expression of genes that favor fatty atrophy and fibrosis and inhibit myogenesis [15].
The most commonly accepted extrinsic mechanism for rotator cuff disease was originally described by Neer in his classic article from 1972, Anterior Acromioplasty for the Chronic Impingement Syndrome in the Shoulder: a Preliminary Report, and has guided clinical approach to management of impingement and rotator cuff tears ever since, although validity of some of these concepts has been challenged in the recent years. Neer suggested that repetitive contact between the rotator cuff tendons and the underside of the coracoacromial arch (which includes the anterolateral acromion, coracoacromial ligament, and the coracoid) results in trauma to the tendon, which produces the clinical entities of subacromial or subcoracoid impingement, and, in its more advanced stages, tendon tears [16]. Acromial morphology (hooked versus flat) and presence of subacromial enthesophytes have also been proposed to be contributing factors to symptomatic cuff disease, and surgical approach directed at increasing the space under coracoacromial arch by way of acromioplasty and coracoacromial ligament release has been advocated [17]. However, recent studies have questioned the benefit of these procedures [18], and attention has been directed to position and dynamic function of the scapula, as a contributor to rotator cuff impingement and tears [19]. Therefore, postural abnormalities and peri-scapular muscle strength have received greater recent attention as potentially contributing risk factor that can and should be addressed in management of rotator cuff disease.
Rotator cuff repair was originally performed with open, and subsequently mini-open, techniques, which have produces good results, including restoration of shoulder strength and function. Advent and popularization of arthroscopy have allowed for a less invasive method of rotator cuff repair, contributing to decreased postoperative pain and more rapid return of motion. Other modern advancements, such as improved instrumentation, as well as stronger and more biocompatible suture and anchor materials, have led to new surgical techniques, such as a double-row rotator repair, which may contribute to better healing and possibly improved outcomes, especially for larger tears. Multiple clinical studies of arthroscopic repair have shown good to excellent results in as many as 90% of patients postoperatively, even including those with large and massive tears [20, 21, 22, 23]. A recent systemic review and meta-analysis by McElvany et al. [24] included 108 clinical studies and showed postoperative clinical outcomes scores improved by an average of 103% of the preoperative scores. However, despite the overall good results, this same study found that 26.6% of the repairs failed to heal. Failure to heal may not (and often does not) affect short-term results, but may lead to deterioration of shoulder function after 2 years post-repair. Risk factors for failure of the rotator cuff tear to heal after surgery include preoperative fatty infiltration of the muscle, older age, and increased tear size. As many as 50% of larger (≥3 cm) tears may fail to heal after repair.
One of the most important predictors for failure of rotator cuff repair, along with tear size, is muscle atrophy and fatty infiltration (Figure 3). Most common system used to classify fatty degeneration of rotator cuff muscles was described by Goutallier et al. [25]. Even small and medium tears are at risk for failure after repair with as little as grade 2 muscle degeneration [26]. Shoulders with more severe (grade 3 or 4) degeneration, where more than 50% of muscle volume is replaced by fat, are at a very high risk of poor outcomes, since, even if tendon repair and healing to bone is achieved, dynamic function of the rotator cuff muscle-tendon unit remains compromised.
Fatty atrophy of the superior rotator cuff. (A) Sagittal MRI view of a right shoulder showing severe fatty degeneration (more than 50% of muscle volume replaced by fat) of the supraspinatus (SS), infraspinatus (IS), and subscapularis (SSC) muscles. (B) Arthroscopic view of the supraspinatus (SS), demonstrating severe muscle atrophy (view from a posterolateral subacromial portal in the right shoulder).
Therefore, due to poor healing potential and low likelihood of restoration of good cuff function, chronic large (3–5 cm) and massive (>5 cm) tears, especially those with Goutallier 2 or greater atrophy, may be considered irreparable. Other types of tears that are considered irreparable include tears with significant retraction of the tendon (medial to the glenoid), poor tendon quality for repair, and poor bone quality at the greater tuberosity attachment site (Figure 4). Attempts at repair of tears with these features should be approached with guarded expectations.
Massive tear of the superior rotator cuff, not amenable to repair. (A) Note poor tissue quality of the tendon stump, and retraction medial to the glenoid rim. (B) Despite extensive releases, this tendon stump could not be mobilized even to the medial margin of the greater tuberosity.
Those rotator cuff tears that fail to heal or are irreparable frequently go on to a clinical condition called cuff tear arthropathy (CTA) (Figure 2). This is a specific form of shoulder arthritis resulting from rotator cuff deficiency. Due to the failure and absence of superior restraint, the humeral head typically migrates superiorly, and eventually articulates with the acromion. Over time this leads to wear of the acromion, destruction of the humeral head cartilage, and eventually the glenoid cartilage as well. Patients typically present with significant pain, weakness, and crepitus with range of motion, and sometimes even pseudoparalysis—severe inability to elevate the shoulder. Once advanced CTA develops, the only surgical solution available to treat it (other than fusion of the shoulder joint) is a reverse total shoulder replacement (Figure 5).
Reverse shoulder replacement in a 60 year-old man, performed for symptomatic advanced cuff-tear arthropathy.
The treatment of massive and irreparable rotator cuff tears is challenging. Surgical options include partial repair with marginal convergence, debridement with biceps tenotomy, graft interposition, tendon transfer, reverse total shoulder, and now superior capsular reconstruction. Partial repair of the inferior half of the infraspinatus was originally described by Burkhart et al. in 1994, with the goal restoring a balanced anterior-posterior force couple in the shoulder [27]. Multiple studies which analyzed surgery for massive cuff tears with combinations of partial repair, marginal convergence, debridement, and biceps tenotomy have shown mixed results, typically with good outcomes early on, but persistent strength deficit in elevation, and deterioration of clinical results over time. For example, Shon et al. performed partial repair and marginal convergence techniques in 31 patients and found initial improvement in clinical outcome scores, whereas 2-year follow-up showed a dissatisfaction rate of 50% [28]. Fatty infiltration of the infraspinatus was found to be a negative predictor of outcome in these patients.
Graft interposition techniques to bridge irreparable rotator cuff defects have been described using autograft, allograft, xenograft, and synthetic materials. A systematic review of these techniques found a lack of high quality comparative studies. The limited studies available show improvement in clinical outcomes in all graft types [29], with allograft, xenograft, and synthetic grafts having the appeal of no harvest site morbidity, compared to autograft. On the other hand, significant inflammatory reactions have been reported with the use of xenografts as well as allografts [30], and therefore caution must be used. Just as with other surgeries for massive cuff tear, significant fatty atrophy leads to significantly lower healing rates after graft interposition repairs. Finally, interpositional grafts may need to be placed through an open approach, which runs the increased disk of damage to the deltoid muscle, potentially making subsequent revision surgery more difficult and less successful. In summary, due to lack of high quality comparative studies on the use of graft interposition for cuff repair, the potential benefits of this procedure must be weighed against the cost, risks, and potential future complications of this approach.
Several tendon transfer procedures have been described for the treatment of massive irreparable rotator cuff tears. Tendon transfers are typically performed in younger patients without glenohumeral arthritis and good range of motion. The most common transfers used for posterosuperior tears are latissimus dorsi and lower trapezius transfers. Clinical studies show latissimus dorsi transfer provides significant pain relief after tendon transfer, whereas functional results are more unpredictable [31]. Lower trapezius transfer anatomically provides a more direct line of pull compared to latissimus dorsi transfer; however, limited clinical evidence is available to show improvement in pain and function.
Reverse total shoulder arthroplasty (RTSA) is a semiconstrained reverse ball and socket prosthesis which helps improve the biomechanical efficiency of the deltoid muscle by lengthening its lever arm. The design provides inherent glenohumeral stability and lowers the humeral head to increase deltoid tension, which allows this muscle to elevate the arm without a functional rotator cuff. While elevation is typically restored after RTSA, active rotation of the shoulder is not as easily recovered as it relies on presence of the anterior-posterior components of the cuff. Overall, clinical studies have shown significant improvements in pain, motion, and functional scores in patients treated for cuff-tear arthropathy. However, implant longevity is a concern, as are functional limitations imposed by this surgery. Due to these limitations, reverse shoulder arthroplasty is typically reserved for patients in their 60s, 70s, and older [32].
The main reason to consider superior capsule reconstruction (SCR) is as an alternative to reverse shoulder arthroplasty or tendon transfers in patients with irreparable superior rotator cuff tears, with or without early cuff tear arthropathy. In this procedure a graft tissue is attached to the superior glenoid and the greater tuberosity, thereby spanning the superior aspect of the glenohumeral joint (Figure 6). The biomechanical rationale behind this surgery is debated. One proposed rationale is a tenodesis effect between the glenoid and the humeral head, which helps regain the stabilizing effect to the glenohumeral articulation normally conferred by the superior capsule and the rotator cuff [2]. This has been called the “reverse trampoline” effect. The other proposed mechanism is that the inserted graft acts a spacer between the humeral head and the underside of the acromion, essentially keeping the head depressed by way occupying the space above it. Biomechanical cadaveric studies by Mihata and colleagues have shown that SCR does restore superior translation to physiologic conditions [33]; and also that increased thickness of the graft improves stability [34]. These studies lend credence to both theories regarding biomechanical function of SCR; indeed both factors may be at play.
Schematic drawing, showing a shoulder with a normal superior rotator cuff (A), a large and irreparable defect of the superior cuff (B), and after a SCR (C and D).
Indications for this surgery currently include physiologically young (absolute age has not been determined) and relatively active patients with symptomatic irreparable superior rotator cuff, with intact anterior-posterior force couples, and no or minimal glenohumeral arthritic wear. Young patients with moderate cartilage wear and symptoms primarily related to cuff function may be considered for SCR, in lieu of RTSA, but guarded expectation are warranted with more severe arthritic wear. SCR may also be an attractive option for previous failed cuff repair, in a setting of poor tissue quality, fatty infiltration, and other factors that may result in tear irreparability.
Absolute contraindications include infection, neuropathic disease of the shoulder, and neurologic disorders significantly affecting function of the deltoid muscle. Relative contraindications include advanced arthritis, tears of the anterior/posterior rotator cuff, as well as unwillingness or inability to comply with postoperative immobilization and rehabilitation protocol.
Arthroscopic reconstruction using tensor fascia lata was initially proposed by Mihata et al. [2]. Several other authors have reported SCR using acellular dermal allograft [35, 36, 37, 38, 39]. An arthroscopic technique is typically used for this procedure, but an open technique may be used in cases of difficult arthroscopic exposure or for surgeons less familiar with arthroscopic techniques. We describe our preferred technique for arthroscopic superior capsular reconstruction.
Surgery is typically performed in an ambulatory setting, under combination general and regional anesthesia. After induction of anesthesia, and prior to positioning (with the patient supine on the operating table), the shoulder should be examined for passive motion and stability. Manipulation of the shoulder to regain motion should be performed as needed. We prefer a beach-chair position with the arm supported by a hydraulic arm positioner device, but a lateral decubitus with balanced suspension-traction may also be used.
Standard posterior portal is used to enter the glenohumeral joint, and an anterior portal is established in the rotator interval. A thorough diagnostic arthroscopy of the glenohumeral joint is performed, and pathologic lesions are addressed as needed. Particular attention must be paid to the integrity of the subscapularis tendon, which needs to be repaired if significantly torn. If the biceps tendon is still present in the joint (more often than not there is a chronic tear and absence of the long head), it needs to be removed from the superior glenoid, so that it does not block graft placement; a tenotomy or tenodesis is performed. Any loose bodies should be removed, and synovectomy is performed as needed. Chondroplasty may be performed for frayed and unstable cartilage flaps on the humeral head and glenoid.
The camera is then repositioned into the subacromial space. Subacromial portals are created, typically one anterolaterally and one posterolaterally. A bursectomy is performed, and the rotator cuff tear is then carefully evaluated, characterized and mobilized, ensuring that a repair is not possible or not advisable. A superior capsular reconstruction is considered if there is a massive full-thickness tear of the supraspinatus, without or without infraspinatus tear, that cannot be repaired, and the glenohumeral joint does not show severe degenerative changes (Figure 7).
Massive and irreparable rotator cuff tear in the left shoulder of a 70 year old active male (view from posterolateral portal). (A) Note severely retracted massive tear of the superior cuff (SS and IS), with relatively normal articular cartilage both on the glenoid and the humeral head. (B) Even after extensive releases, the tendon stump is not adequately mobile for primary repair (HH—humeral head; G—glenoid).
Once a decision is made to perform a SCR, an acromioplasty should be performed, to increase working space for graft placement and fixation, and also to decrease the risk of graft tissue abrasion postoperatively [40]. Any osteophytes off the inferior aspect of the AC joint need to be resected as well (Figure 8). We always attempt to preserve the CA ligament, if possible, so as not to disrupt the coracoacromial arch.
An inferior osteophyte (OP) is being resected off the distal clavicle (DC), to avoid impingement and abrasion of the graft postoperatively.
We also prefer at this time to place #2 braided sutures into the upper borders of the intact cuff posteriorly (teres minor or infraspinatus) and anteriorly (subscapularis or intact anterior fibers of the supraspinatus); these are used, after graft fixation, to repair the native cuff to the patch, side to side. Additionally, if there is any significant cuff tissue remaining medially, overlying the glenoid rim, it can be tagged with a #2 suture through a Neviaser portal, and pulled up for better visualization of the superior glenoid (Figure 9).
(A) A penetrating suture passer is inserted through the Neviaser portal and is used to pass a tagging suture through the rotator cuff tendon stump. (B) The rotator cuff can then be pulled up, to allow better visualization of and instrumentation on the glenoid neck.
Any residual soft tissue on the superior glenoid neck and greater tuberosity is removed using a motorized shaver and/or electrocautery wand. To maximize healing potential, the superior glenoid neck and greater tuberosity are burred down to bleeding bone.
Medial anchors are placed on the superior glenoid, approximately 2–4 mm medial to the rim, taking care to ensure good bone purchase and avoid intraarticular penetration. Anchors are placed as far anterior and posterior as possible to provide adequate spread and coverage for the medial graft fixation on the glenoid. Typically two anchors, each double loaded with a #2 braided suture, are placed, in the region between the 10 and 2 o’clock positions (Figure 10A and B), but a third anchor may need to be added for very large defects (Figure 10C). Appropriate trajectory for anchor placement should be confirmed prior to drilling, and can typically be achieved from the anterior, posterior and Neviaser portals.
Glenoid anchors. Each one is double-loaded with a #2 braided suture. Note the anchor position approximately 2–4 mm medial to the rim, and the trajectory of insertion (away from the articular cartilage). The spread between the anchors can be narrow (A) for smaller defects, or wide (B) for larger ones. Sometimes three anchors may need to be placed (C), for massive tears involving both the SS and IS. In this case, a Neviaser portal helps with proper trajectory for the middle anchor, as shown by the spinal needle.
On the humeral head, graft fixation is accomplished using a double row transosseous equivalent technique. Prior to graft passage, medial row greater tuberosity anchors placed, just lateral to the articular margin (Figure 11). We prefer to use anchors preloaded with #2 suture-tape, non-sliding. As on the glenoid, two anchors are typically used, but a third one may be needed in large shoulders with large defects.
Medial row greater tuberosity (GT) anchors are inserted. The anterior anchor is placed just posterior to the bicipital groove, and the posterior anchor is at the posterior-most extent of the exposed tuberosity. Both are pre-loaded with a suture-tape, and placed adjacent to the articular margin of the humeral head. Note how the surface of the GT has been decorticated down to bleeding bone.
Once all the anchors are placed, distances between them are measured. First the anterior-posterior distance is measured for the glenoid anchors and tuberosity anchors. Then the medial-lateral distance is measured between the glenoid and tuberosity anchors, obtaining one measurement anteriorly, and one posteriorly. A calibrated probe is used to make these measurements (Figure 12). In our opinion, in order to obtain the graft size that will provide appropriate stabilizing affect without overtightening the glenohumeral articulation, the shoulder should be positioned in neutral rotation and approximately 20–30° of abduction for the measurement, and during subsequent graft fixation.
Measuring distances between the anchors using a calibrated probe. (A) Distance between the glenoid anchors. (B) Distance between the medial GT anchors. (C) Distance between the glenoid and GT anchors (posterior, viewing from the anterolateral portal).
Next the graft if prepared. We use an acellular human dermal graft (Arthroflex by Arthex, Inc., Naples, FL), but an autograft, such as tensior fascia lata, may also be harvested and used. Whichever graft is used, it is now sized and prepared on the back table. The graft is cut to allow a 5 mm margin medially, anteriorly and posteriorly and a 10 mm margin laterally. The dimensions of the anchor configuration are then carefully marked on the graft using a marking pen (Figure 13).
Graft measurement. It is important not to cut the graft too short. 5 mm extra is left on the medial, anterior, and posterior edges, whereas laterally 10 mm extra distance is left to allow coverage over the GT footprint.
At this point, all the sutures must be brought out through one of the subacromial portals in preparation for graft passage. We prefer to view from the posterior or posterolateral portal, and use the anterolateral portal for graft passage. Sometimes this portal must be slightly increased in size, and a flexible cannula, which can be cut along one of its sides (such as the Arthex Passport) can be helpful.
The graft is brought close to the shoulder, carefully supported on a sterile Mayo stand. The sutures from the glenoid anchors are passed through the medial edge of the graft. Simple configuration can be used, but we prefer to place each sets of sutures in a criss-crossing mattress configuration (one vertically and one horizontally), creating a Mason-Allen type configuration. One limb from each suture set is tied to a limb from another suture set (off a different color), and the knot tails are cut. This leaves two suture limbs (one of each color) on the anterior-medial and posterior-medial edges of the graft, which, when tensioned, create a pulley effect on the graft, allowing it to be drawn into the joint (Figures 14 and 15).
Suture placement into the graft prior to shuttling. Glenoid sutures are placed in a horizontal and vertical mattress configurations, perpendicular to each other. Laterally, we prefer to place a suture-loop (Arthrex Fiberlink), for subsequent shuttling of suture-tapes from the GT medial row anchors.
Model demonstration of the step-by-step process of glenoid suture placement and tying. (A) All suture limbs from each anchor are placed in a mattress configuration, perpendicular to each other. (B) One limb from each suture is tied to a limb from the other suture (different color), and this creates a double-pulley system, which helps shuttle the graft to its attachment points on the glenoid. (C) Final construct, with all glenoid sutures tied.
At this time it is possible to either place the tuberosity medial row sutures through the graft, or instead place a suture loop (such as Arthrex Fiberlink) which would aide with the passage of those sutures later. The advantage of the latter approach is minimizing suture traffic in the lateral subacromial portal, and avoiding suture entanglement. We prefer this technique (Figure 14), and temporarily park the medial row tuberosity sutures in the anterior and posterior portals, while the graft is being passed.
The suture pulley system previously created on the medial side of the graft with the glenoid sutures is now tensioned. The graft may need to be partially folded to allow it to pass through the cannula, or the cannula may be removed (if it was pre-cut). Also, a blunt tissue grasper can be used to pinch the graft medially to ease the delivery and transport of the graft through the cannula. The graft is visualized entering the joint, and moving medially until it sits flush on the superior glenoid neck, covering the rim (Figure 16A and B). It may be necessary to help unfold the anterior and posterior edges of the graft once its fully inside, in case they get folded in.
Arthroscopic view of graft fixation to the glenoid. (A) The graft is pulled in using the double-pulley system, which is created by tying one limb of each suture to the other one from the same anchor (white arrows); the remaining limbs act as pulley sutures (black arrows), to cinch the graft onto the superior glenoid rim. (B) Note the ability to pull up the remnant of the superior cuff, with a previously placed free suture, via the Neviaser portal, for improved visualization. (C) After the sutures from the glenoid anchors are tied, securing the graft to the glenoid, the remnant cuff tissue can be tied down to the graft, using those suture tails. This creates a nice biologic seal over the medial part of the SCR construct.
The sutures from the glenoid anchors are then tied arthroscopically to secure the graft to the glenoid neck. The tails of those sutures may be passed up through the remnant of the native cuff, to bring it down to the medial edge of the graft, helping create a biologic seal over this area (Figure 16C).
Then the tuberosity medial row sutures are passed through the graft using the previously pre-loaded suture-loop, if they haven’t been already placed outside the shoulder. Both limbs of the sutures from the medial GT anchors are passed through the graft, from inferior to superior, one at the anterior and one at the posterior pre-determined spots (Figure 17A). Finally, these suture-tapes are brought over the lateral-most extent of the graft in a criss-cross fashion, and secured just past the lateral margin of the tuberosity with knotless anchors (Figure 17B–D). Prior to setting final tension and fixating the graft laterally, proper shoulder position of neutral rotation and slight abduction (20–30°) needs to be ensured.
Graft fixation to the humeral head. (A) Suture-tapes from the medial row greater tuberosity anchors are passed up through the graft, using the previously placed suture-loop (left shoulder, view from the anterolateral portal; AA—anterior anchor, PA—posterior anchor, GT—greater tuberosity); (B) Suture tapes are criss-crossed and secured just past the lateral margin of the tuberosity with knotless anchors, providing excellent compression of the graft over the tuberosity footprint. (C) If a small “dog-ear” is noted after lateral graft fixation, a suture preloaded into the lateral-row anchor can be used to tie it down. (D) Model demonstration of graft fixation to the humeral head.
Once the graft is secured medially and laterally, side-to-side margin convergence sutures are placed to secure the graft to the intact cuff (Figure 18A and B ). Pre-placed sutures are helpful for this, as discussed above. Typically two side-to-side sutures are used posteriorly, to connect the graft to the intact part of the infraspinatus or to the teres minor. Anteriorly, if the fixation is to the intact remaining supraspinatus, two sutures may be used as well (Figure 18C); however, if there is no supraspinatus left, and fixation is to the upper border of the subscapularis, no more than one suture should be used, as laterally as possible, to avoid over-constricting the rotator interval. If the distance between the anterior edge of the graft and the upper border of the subscapularis is too great, no margin convergence sutures are placed here.
Side-to-side repair to the intact cuff and completion of the SCR. (A) Sutures are passed through the graft and adjacent intact cuff. (B) Sutures are then tied, providing close approximation between the graft and native tissue. (C) Superior view from the Neviaser portal, showing a completed SCR, with excellent coverage of the joint by the graft and native cuff, repaired to the graft.
The shoulder is then taken through a full range of motion to ensure no signs of impingement. And residual spurs on the acromion, or osteophytes off the inferior distal clavicle should be resected (Figure 8).
We follow the same protocol for our SCR cases as for our large rotator cuff repair cases. A shoulder immobilizer sling is worn for 6 weeks, with or without an abduction pillow. Passive range of motion exercises are started at 4–6 weeks postoperatively, active-assisted motion is allowed at 6–8 weeks, and full active motion is allowed after 8 weeks. Strengthening progresses after 12 weeks, and return to activities which require overhead lifting is allowed no earlier than 16 weeks. Typical full return to activities is allowed 6 months postoperatively.
Published reports of clinical outcomes following superior capsular reconstruction thus far have been limited to one study, but more such studies are currently either in data collection or already in preparations to report outcomes. In 2013, Mihata et al. reported a case series of 24 shoulders (23 consecutive patients), treated with SCR using fascia lata autograft, with minimum 2-year follow-up [2]. At an average follow-up of 34 months (24–51 months), mean active elevation increased from 84 to 148° and mean external rotation increased from 26 to 40°. All clinical outcomes scores improved significantly, with American Shoulder and Elbow Surgeons score (ASES) score going up from an average of 23.5 to 92.9. Furthermore, imaging showed acromiohumeral distance increased from 4.6 to 8.7 mm, on average. No procedure-related complications were reported [2].
In the United States, most surgeons prefer to use a dermal allograft (Arthrex Arthroflex), which is a thick (3 mm) and durable patch, which requires minimal preparation time and is relatively easy to handle. Several technical reports using this graft have been published, including those by Hirahara and Adams, Petri et al., Tokish and Beicker, and Burkhart et al. [36, 37, 38, 39], but clinical data on the outcomes of this approach is lacking in the published literature. However, personal communication with a number of surgeons currently performing SCR using the dermal allograft patch produced reports of high patient satisfaction rates, excellent improvement in function and pain levels in the short term, and low risk of complications. One of our personal communications has been with a surgeon who now has data on 20 SCR procedures, with a minimum follow-up of 3 months and up to 1.5 years, and reports that Visual Analogue Scale (VAS) scores decreased on average from 6–9 to 0–3 range, while ASES scores went up from the 20–30 range to the 70–90 range. No complications were reported in this patient group (personal communication with Dr. Kevin Kaplan, Jacksonville Orthopedic Institute, Jacksonville, FL).
Large irreparable rotator cuff tears in younger and active patients continue to pose a significant clinical challenge to orthopedic surgeons. Arthroplasty treatment option with a reverse shoulder replacement is not ideal in this patient population. Mihata et al. [33] have shown in biomechanical cadaveric studies that a graft reconstruction can restore superior glenohumeral translation when the graft is attached to the glenoid medially and humeral head laterally. However, many technical aspects of this procedure have not been well studied, such as ideal suture and anchor configuration medially or laterally, ideal graft tissue (allograft versus autograft), ideal graft thickness, or ideal tensioning technique.
In the immediate future, we will need larger clinical studies with short, medium, and long-term outcome data demonstrating the effectiveness of superior capsular reconstruction. Radiographic follow-up studies are needed to document graft incorporation or deterioration after this surgery, as well as to monitor the acromiohumeral distance in this patient population. Clinical indications and contraindications, as well as the ideal patient population, for this procedure need be better defined.
Superior capsular reconstruction is a novel technique that may provide a potentially promising solution to a tough problem in the shoulder region. The procedure should be considered for active and physiologically young patients with high functional demand on their upper extremity, and an irreparable rotator cuff tear, and should be performed by surgeons experienced in treating shoulder pathology. More clinical studies are needed before we can advocate widespread use of this procedure in general orthopedic practice.
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\n\nOut of all of the publishing options available to researchers, why choose to contribute your research to an IntechOpen Edited Volume? The reasons are simple. IntechOpen has worked exceptionally hard over the past years to fine tune the Open Access book publishing process and we continue to work hard to deliver the best for all of our contributors. The quality of published content is of utmost importance to us, followed closely by speed, and of course, availability and accessibility. To view current Open Access book projects that are Open for Submissions visit us here.
\n\nQUALITY CONTENT
\n\nOver the years we have learned what is important. What makes a difference to the researchers that work with us, what they value. Something that is very high not only on their lists, but our own, is the quality of the published content.
\n\nOur books contain scientific content written by two Nobel Prize winners, two Breakthrough Prize winners and 73 authors who are in the top 1% Most Cited.
\n\nWith regular submission for coverage in the single most important database, the Book Citation Index in the Web of Science™ Core Collection (BKCI), and no rejected submissions to date, over 43% of all Open Access books indexed in the BKCI are IntechOpen published books.
\n\nIn addition to BKCI, IntechOpen covers a number of important discipline specific databases as well, such as Thomson Reuters’ BIOSIS Previews.
\n\nACCESS
\n\nThe need for up to date information available at the click of a mouse is one thing that sets IntechOpen apart. By developing our own technologies in order to streamline the publishing process, we are able to minimize the amount of time from initial submission of a manuscript to its final publication date, without compromising the rigor of the editorial and peer review process. This means that the research published stays relevant, and in this fast paced world, this is very important.
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