Patient-related risk factors of post-ERCP pancreatitis (Adapted from ref. Dumonceau et al., 2010).
\r\n\tThis field has grown exponentially over the past decade resulting in less postoperative pain, risk of complications, and recovery times. Arthroscopy has evolved from a diagnostic tool to a therapeutic tool capable of treating a wide range of injuries and disorders in most of the joints. Many injuries, particularly those that at one time would have been career-ending for athletes, can now be addressed with arthroscopy allowing a quicker return to a competitive level. While arthroscopy has resulted in an overall decrease in morbidity compared with open techniques, it is still an invasive procedure and inherently involves risks.
\r\n\r\n\tWith this book, we attempt to summarize the most common arthroscopic procedures, diagnosis, risks, and complications.
\r\n\tAll of the above aspects are addressed in this book, which describes the current applications of arthroscopy, explaining the mechanisms of injury for each condition, and describing the role of arthroscopy in diagnosis and treatment.
\r\n\t
Despite the significant development in endoscope technology and in availability of endoscopic accessories and the spreading of well structured ERCP training the incidence of ERCP-related acute pancreatitis has been little changed in the last three decades. One of the explanations of this contradiction may be that post-ERCP pancreatitis occurs nowadays more often in case of therapeutic intervention compared to the diagnostic ERCP and the need for solely diagnostic ERCP is rapidly declining due to the development of less invasive imaging methods such as magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasonography (EUS). ERCP has become an almost exclusive therapeutic procedure.
\n\t\tEndoscopic retrograde cholangiopancreatography (ERCP) has the greatest potential for complications among the gastrointestinal endoscopic procedures. The most common complication is acute pancreatitis with an overall incidence of 2-10 %, which can reach even 30 % in the presence of certain risk factors. The post-ERCP pancreatitis is most often mild, or less commonly moderate, but in about 10% of cases (about 0.4-0.6 % of the procedures performed) it is severe and potentially fatal. The mortality rate is about 0.1-0.5 %. Furthermore asymptomatic hyperamylasemia occurs in 35-70 % in patients undergoing ERCP. The wide interval of the published incidence of pancreatitis can be explained by and, depends on the criteria used for diagnosis, the type and duration of follow-up of patients involved in the studies, the levels of endoscopic expertise and, the frequency of patients- and procedure-related risk factors in the patient population (Cotton et al. 2009).
\n\t\tA transient elevation in the serum amylase concentration without clinical signs of pancreatitis is common following ERCP and abdominal pain is also a frequent complaint due to distension caused by intestinal retention of air insufflated during the procedure. Therefore clear definition is mandatory for exact evaluation of clinical trials, for comparing the results of different publications and for the standardised management in the prevention and treatment of ERCP related pancreatitis.
\n\t\t\tThe current definition is based on an attempt at consensus in 1991 (Cotton et al.). According to this proposal post-ERCP pancreatitis was originally defined as „clinical pancreatitis with serum amylase at least three times normal at more than 24 hours after the procedure, requiring hospital admission or a prolongation of planned admission”. On the basis of this definition the widely excepted criteria for the diagnosis of post-ERCP pancreatitis are the followings: pancreatic-type abdominal pain and symptoms with onset after ERCP and severe enough to require hospital stay or to extend the length of stay of already hospitalised patients, serum amylase and/or lipase at least 3 times higher than the upper limit of normal values in 24 hours after the procedure, and/or CT/MRI consistent with the diagnosis of acute pancreatitis.
\n\t\t\tThe severity of attack was graded by the above consensus report as mild, moderate and severe. A mild post-ERCP pancreatitis was defined as a need for hospital stay up to 3 days, a moderate pancreatitis was defined as a need for hospital stay for 4-10 days, and a severe pancreatitis as more than 10 days with a significant complication. The European Society of Gastrointestinal Endoscopy (ESGE) guideline recommends a more specific grading system of the severity of pancreatitis for the future (Dumonceau et al. 2010). The Atlanta classification can also be used for the estimation of severity of the post-ERCP pancreatitis, on the basis of the absence or presence of local (documented by CT) or systemic complications, independently of the duration of the hospital stay.
\n\t\tPathomechanism of post-ERCP pancreatitis is of multifactorial nature, but it has not been fully understood yet. It seems to be an inflammatory response to mechanical, hydrostatic, thermal, bacterial and chemical insults that results from canulation and other instrumentation of the papilla and injection of contrast medium into the pancreatic duct. These initiating factors may act independently or in combination.
\n\t\t\t\n\t\t\t\tMechanical trauma: repeated cannulation attempts or prolonged manipulation around the papillary orifice may cause injury of the pancreatic sphincter or proximal pancreatic duct and may lead to mechanical obstruction due to oedema of the pancreatic sphincter or to prolonged spasm in patients with sphincter of Oddi hypertension.
\n\t\t\t\n\t\t\t\tHydrostatic factor: pressure increase in the pancreatic duct may be related to overinjection of contrast medium (parenchymography) or to pancreatic manometry without distal aspiration. The consecutive capillary endothelial injury leads to an increase in capillary permeability. It has been suggested that this capillary injury might be mediated by oxygen-derived free radicals.
\n\t\t\t\n\t\t\t\tThermal injury: electrocautery current may produce edema of the pancreatic orifice and thermal damage of the periampullary acinar cells. Coagulation or blended current causes more tissue injury than cutting current.
\n\t\t\t\n\t\t\t\tInfection: bacterial injury from contaminated endoscope channel or accessories may occur.
\n\t\t\t\n\t\t\t\tChemical factor: injection of contrast medium into the pancreatic duct may result in chemical injury. High osmolarity contrast agents are thought to play a role in the induction of hyperamylasemia, although a meta-analysis (George et al. 2004) could not confirm it.
\n\t\t\t\n\t\t\t\tEnzymatic factor: intestinal content may activate intrapancreatic proteolytic enzymes.
\n\t\t\tThe above initiating factors lead to autodigestion due to premature intracellular activation of pancreatic proteolytic enzymes, and to release of inflammatory cytokines producing both local and systemic effects (Demols & Deviere 2003, Karne & Gorelick 1999). The severity of pancreatitis is determined by the intensity of the inflammatory cascade and systemic response. The process itself is believed the same as for other forms of acute pancreatitis.
\n\t\tStratification of patients into low or high risk categories is important pre-investigational information to take the potential benefit and risk of procedure into account, to consider patient referral to a tertiary centre, and for selection of prophylactic measures. A number of risk factors acting independently or in combination have been identified. They can be categorised as patient related, procedure related, and investigator related risk factors.
\n\t\t\tA multivariate analysis of prospective studies found as significant patient-related risk factors the followings: young age, female gender, suspected sphincter of Oddi dysfunction, previous post-ERCP pancreatitis, recurrent acute pancreatitis, and lack of evidence of chronic pancreatitis (\n\t\t\t\t\t\tFreeman & Guda, 2004\n\t\t\t\t\t). The European Society of Gastrointestinal Endoscopy (ESGE) guideline further differentiates between definite and likely risk factors based on the strength of evidence from prospective studies (Dumonceau et al., 2010) (Table 1.). These risk factors can act synergistically, putting patients at high risk for post-ERCP pancreatitis.
\n\t\t\t\tDefinite risk factors | \n\t\t\t\t\t\t
Suspected sphincter of Oddi dysfunction | \n\t\t\t\t\t\t
Female gender | \n\t\t\t\t\t\t
Previous pancreatitis | \n\t\t\t\t\t\t
Likely risk factors | \n\t\t\t\t\t\t
Younger age | \n\t\t\t\t\t\t
Non-dilated extrahepatic bile ducts | \n\t\t\t\t\t\t
Absence of chronic pancreatitis | \n\t\t\t\t\t\t
Normal serum bilirubin | \n\t\t\t\t\t\t
Patient-related risk factors of post-ERCP pancreatitis (Adapted from ref. Dumonceau et al., 2010).
The association of these predictors to post-ERCP pancreatitis proved to be the strongest in patients with known or suspected sphincter of Oddi dysfunction with a complication rate of 10-30 %. All of the risk factors are independently important, but they may have a cumulative effect. In a prospective multicentre study (Freeman et al. 2001) the highest risk (42%) was found in the following combination of the predictors for post-ERCP pancreatitis: female patients, normal serum bilirubin level, suspected sphincter of Oddi dysfunction, and difficult bile duct cannulation. It can be postulated that a prolonged pancreatic sphincter spasm may be an important common factor in the induction of pancreatitis in the group of patients with increased risk for post-ERCP pancreatitis, and that this group of patients have a lower threshold for developing pancreatitis after ERCP.
\n\t\t\t\tThe higher risk in younger age might depend on the lack of age-related atrophy of the pancreatic glands and on the higher prevalence of sphincter of Oddi dysfunction in young people, predominantly in females. Similarly to the aging, the protective role of chronic pancreatitis can be explained by atrophy and decreased enzymatic activity. Patients with normal serum bilirubin and non-dilated stonefree bile ducts reported as predictors for developing post-ERCP pancreatitis may also have sphincter of Oddi dysfunction not having been taken into consideration in the diagnosis, especially regarding patients complaining also biliary pain. A history of acute pancreatitis independently of the etiology is the second most important risk factor after sphincter of Oddi dysfunction, and it should be taken into consideration before planning an ERCP.
\n\t\t\tProcedure-related risk factors are similarly important as patient-related factors in determining the incidence and severity of post-ERCP pancreatitis (Fig 1.). Various procedures are associated with higher risk of post-ERCP pancreatitis (Table 2.), most of them documented by multivariate analyses. For example role of papillectomy has not been analysed, but it can be considered as a definitive risk factor on the basis of prospective studies.
\n\t\t\t\tDefinite risk factors | \n\t\t\t\t\t\t
Pancreatic duct cannulation and contrast injection | \n\t\t\t\t\t\t
Multiple attempts of cannulation | \n\t\t\t\t\t\t
Precut sphincterotomy | \n\t\t\t\t\t\t
Endoscopic papillectomy | \n\t\t\t\t\t\t
Other risk factors | \n\t\t\t\t\t\t
Balloon dilation of the sphincter | \n\t\t\t\t\t\t
Sphincter of Oddi manometry | \n\t\t\t\t\t\t
Pancreatic sphincterotomy | \n\t\t\t\t\t\t
Pancreatic brush cytology | \n\t\t\t\t\t\t
Failure to clear bile duct stones | \n\t\t\t\t\t\t
Difficult or failed cannulation | \n\t\t\t\t\t\t
Procedure-related risk factors of post-ERCP pancreatitis.
\n\t\t\t\t\tRepeated attempts at cannulating, also without pancreatic duct contrast injection is associated with high incidence of pancreatitis. This fact supports that papillary edema and sphincter spasm, rather than hydrostatic ductal and contrast agent injury are the major factors in the induction of post-ERCP pancreatitis. The risk rate seems to progressively increase with the number of attempts. More than 10 cannulation attempts can increase the risk of pancreatitis about 15-fold (Testoni et al. 2010).
\n\t\t\t\tThe contrast injection itself can induce pancreatitis due to hydrostatic injury from pancreatic duct overfilling, which is the most pronounced in cases of parenchymography. The use of lower ionic contrast agents does not result in lower frequency of pancreatitis than that of the conventional ones.
\n\t\t\t\t\n\t\t\t\t\tPre-cut sphincterotomy is associated with a threefold increase of post-procedure pancreatitis, however the risk is likely mainly investigator dependent and seems to be lower in experts hands. Moreover, early pre-cut may be safer than delayed pre-cut performed after multiple cannulation attempts. The overall risk of pancreatitis after pre-cut sphincterotomy is less than after repeated attempts at standard cannulation. Out of the two techniques of needle knife precut, fistulotomy where the precut is separate from the papillary orifice, seems to be accompanied with less pancreatitis than precut starting at the papillary orifice (Mavrodiannis et al. 1999), although high level evidence fails to support the preference of fistulotomy.
\n\t\t\t\tEndoscopic retrograde cholangiopancreatogram of a young woman with gallbladder stones. Non-dilated bile ducts, young age, and female gender represent patient related risk factors, and contrast injection into the pancreatic duct a procedure related risk factor for post-ERCP pancreatitis.
Pancreatitis occurs after endoscopic papillectomy performed like a snare polypectomy using a side-viewing duodenoscope in 15-20 %. Therefore papillectomy (ampullectomy) should perform only by well-trained and experienced endoscopists. The incidence and severity of this complication can be significantly reduced by prophylactic pancreatic duct stenting (Wong, 2004). Pancreatitis caused by stenosis of the pancreatic duct orifice can also be a late complication after papillectomy (Norton et al., 2002).
\n\t\t\t\tBiliary sphincterotomy itself is not associated with an increased risk of pancreatitis. Currently the use of pure cut current is advisable, because it causes less tissue injury and edema than coagulation current. On the contrary to biliary sphincterotomy balloon dilatation of the intact biliary sphincter has been associated with a high incidence of pancreatitis, therefore its use is not advisable in the presence of patient-related risk factors, especially in patients with sphincter of Oddi hypertension. Large diameter biliary stent without sphincterotomy can also induce pancreatitis due to compression of the pancreatic sphincter (Tarnasky et al., 1997). On the contrary, biliary-stent exchange in sphincterotomised patients causes less-frequent pancreatitis compared to other ERCP procedures (Cotton et al. 2008).
\n\t\t\t\t\n\t\t\t\t\tSphincter of Oddi manometry using standard perfusion catheter is associated with a substantial incidence of pancreatitis. The risk can be significantly reduced by using modified triple lumen catheter with simultaneous aspiration or by using a microtransducer catheter. In two randomised controlled studies the incidence of post-ERCP pancreatitis was found using the alternative catheters in comparison with the standard perfusion catheter 3.0% vs. 23.5 % and 3.1% vs. 13.8 % (Sherman et al. 1990, Wehrmann et al. 2003).
\n\t\t\t\t\n\t\t\t\t\tPancreatic sphincterotomy was associated with high risk of pancreatitis in a recent prospective multicentre study only in univariate analysis (Testoni et al., 2010), in agreement with some earlier reports (Freeman et al., 2001, Cheng et al. 2006). As independent risk factor proved have to been only minor papilla sphincterotomy.
\n\t\t\t\tWhat other procedure risk factors concerns, pancreatic brush cytology can cause pancreatitis due to edema in consequence of mechanical trauma of the pancreatic duct. In case of failure to clear the bile duct during ERCP residual stones can induce biliary pancreatitis.
\n\t\t\tData about a potential relationship between post-ERCP pancreatitis incidence and endoscopist’s experience in the technique defined as annual case volume (the median number of ERCPs per endoscopists/year) are conflicting. Endoscopist’s inexperience and trainee participation may be associated with a higher incidence as it was shown in some of the studies, while others could not confirm it. This might be explained by the fact that in high-volume centres there are more patients with high risk for potential post-ERCP pancreatitis and larger number of procedures at higher degree of difficulty.
\n\t\t\tThe purpose of placing a temporary pancreatic duct stent is to sustain the pancreatic outflow in the face of relative obstruction due to edema and sphincter of Oddi spasm caused by manipulations of the papilla. A meta-analysis of eight randomized controlled trials demonstrated that short term pancreatic stent placement reduces the incidence of post-ERCP pancreatitis (Mazaki et al 2010) (Fig. 2.). Sofuni et al (2007) found significant benefit of stent placement only in patients at high risk for pancreatitis, and it seems to be not cost-effective in patients at average risk (Das A et al. 2007). Therefore, the use of prophylactic pancreatic stenting is generally proposed only for patients who are at high risk for developing pancreatitis after ERCP. Similar standpoint is represented also in the recommendation of the ESGE guideline (Dumonceau et al. 2010).
\n\t\t\t\t\tThe effect of pancreatic stent placement on the incidence of post-ERCP pancreatitis according to meta-analysis (Mazaki et al. 2010).
What kind of plastic stent should be used? 3 mm long 3 -5 Fr straight polyethylene plastic stents without internal flanges (for promoting of spontaneous elimination in few days following the insertion) and with one or two external flanges (for preventing proximal migration) are recommended for prophylactic purpose (Fig.3). Stents of 3-Fr and 5-Fr in diameter proved to be similarly effective, but the insertion of 5-Fr stents seems to be easier and faster (Zolotarevsky et al. 2011).
\n\t\t\t\t\tPancreatic stent without internal flanges.
The stent migrates spontaneously into the duodenum within two weeks in most of the cases. Within 5 to 10 days after the stent insertion an X-ray control and, when the stent is in place yet, endoscopic stent removal is recommended because of the risk of stent-induced damage to the pancreatic duct. Adverse events including pancreatitis following stenting of the main pancreatic duct occur in 4.2-4.6 %, but the incidence of pancreatitis after failed cannulation attempts may reach even 65 % (\n\t\t\t\t\t\t\tFreeman et al. 2004\n\t\t\t\t\t\t). Therefore this is a technique for experienced endoscopist.
\n\t\t\t\tData about the effectiveness of pancreatic guide wire placement in the prevention of post-ERCP pancreatitis are still controversial. In patients with difficult bile duct cannulation successful biliary cannulation can be achieved by pancreatic guide wire-assisted technique in more than 70% of the cases (Dumonceau et al. 2010). If this method is used, a pancreatic stent should be placed for prophylaxis of pancreatitis (Fig 4.). For the same reason pancreatic stenting can be useful also in cases in which biliary cannulation remains unsuccessful.
\n\t\t\t\tInsertion of 0.035-inch diameter guide-wire into the papilla directly or advancing the guide-wire through the sphincterotome inserted into the papilla for deep biliary cannulation reduces the risk of post-ERCP pancreatitis due to promotion of selective primary cannulation. This method may namely diminish traumatic injury to the pancreatic duct and hydrostatic pressure increase associated with injection of contrast material. Therefore, the guide wire-assisted technique is advised for deep biliary cannulation by the ESGE guideline (Dumonceau et al. 2010). However, in a prospective randomised trial this technique was associated with a lower rate of post-ERCP pancreatitis only with the exception of cases where the technique was performed in patients with sphincter of Oddi dysfunction or where unintentional pancreas guide wire cannulation occurred (Lee et al 2009).
\n\t\t\t\t\tA case of difficult bile duct cannulation. Following pancreatic guide wire-assisted technique pancreatic stent was placed for prevention of post-ERCP pancreatitis.
Several agents have been tested experimentally and in clinical trials for potential efficacy in the prevention of ERCP induced pancreatitis. Chemoprevention studies have targeted the following mechanism of action: reduction of pancreatic secretion, prevention of intra-acinar trypsinogen activation, interruption of inflammatory cascade, relaxation of sphincter of Oddi, and prevention of infection. The majority of the investigated pharmacological agents appeared promising in initial randomised single-centre clinical studies however, conflicting results were obtained from larger multi-centre trials (Table 3.).
\n\t\t\t\tDrug | \n\t\t\t\t\t\t\tEfficacy | \n\t\t\t\t\t\t
Somatostatin | \n\t\t\t\t\t\t\tConflicting data | \n\t\t\t\t\t\t
Octreotide | \n\t\t\t\t\t\t\tConflicting data | \n\t\t\t\t\t\t
Gabexate mesilate | \n\t\t\t\t\t\t\tConflicting data | \n\t\t\t\t\t\t
Ulanistatin | \n\t\t\t\t\t\t\tConflicting data | \n\t\t\t\t\t\t
Nitroglycerin | \n\t\t\t\t\t\t\tConflicting data | \n\t\t\t\t\t\t
Nifedipin | \n\t\t\t\t\t\t\tNo | \n\t\t\t\t\t\t
Lidocain spray | \n\t\t\t\t\t\t\tNo | \n\t\t\t\t\t\t
Epinephrine spray | \n\t\t\t\t\t\t\tNo | \n\t\t\t\t\t\t
Botulinum toxin intrapapillary | \n\t\t\t\t\t\t\tNo | \n\t\t\t\t\t\t
Ceftazidime | \n\t\t\t\t\t\t\tNeed for more trials | \n\t\t\t\t\t\t
N-acethylcysteine | \n\t\t\t\t\t\t\tNo | \n\t\t\t\t\t\t
Beta-carotene | \n\t\t\t\t\t\t\tNo | \n\t\t\t\t\t\t
Allopurinol | \n\t\t\t\t\t\t\tConflicting data | \n\t\t\t\t\t\t
Glucocorticoids | \n\t\t\t\t\t\t\tNo | \n\t\t\t\t\t\t
Pentoxifylline | \n\t\t\t\t\t\t\tNo | \n\t\t\t\t\t\t
Semapimod | \n\t\t\t\t\t\t\tNo | \n\t\t\t\t\t\t
Acethylhydrolase | \n\t\t\t\t\t\t\tNo | \n\t\t\t\t\t\t
Indomethacin | \n\t\t\t\t\t\t\tYes, but need for more trials | \n\t\t\t\t\t\t
Diclofenac | \n\t\t\t\t\t\t\tYes, but need for more trials | \n\t\t\t\t\t\t
Medications tested for prophylaxis of post-ERCP pancreatitis.
Somatostatin and its long-acting analogue ocreotide affect the exocrine function of the pancreas directly by reducing the secretion of digestive enzymes and indirectly by inhibiting the production of secretin and cholecystokinin. According to a meta-analysis pooling the data from ten high-quality randomised controlled trials it can be concluded, that somatostatin did not influence the overall incidence of post-ERCP pancreatitis (Dumonceau et al. 2010). Although a significant risk reduction of post-ERCP pancreatitis was found in four randomised controlled trial, when somatostatin was administered in continuous infusion for longer than 12 hours, and in two studies, when somatostatin was given as a single bolus, the question is yet open, weather using specific dose-schedules somatostatin might be more efficacious (Arvanatidis et al. 2004).
\n\t\t\t\t\tConcerning the long-acting somatostatin analogue ocreotide the same conclusion can be drawn based on an ad hoc meta-analysis of eight randomised controlled trials (Dumonceau et al. 2010). Octreotide can reduce the ERCP-induced hyperamylasemia, but this effect can only be shown, if endoscopic sphincterotomy is simultaneously performed (Tulassay et al. 1997). Octreotide increases namely the tone of the sphincter of Oddi, and therefore this partial beneficial effect of the reduced enzyme secretion may be effective only with sphincterotomy together. Some data suggest that the effect of octreotide may be dose-dependent and more than 0.5 mg of octreotide may be beneficial (Zhang Y et al. 2009), but it should yet be clarified in future studies.
\n\t\t\t\tAntiprotease agents were tested for prophylaxis of post-ERCP pancreatitis with the purpose of prevention of intra-acinar trypsinogen activation to trypsin and that of the subsequent inflammatory cascade. Gabexate mesilate in six randomised controlled trials, while ulanistatin in four randomised controlled trials have been evaluated. Furthermore, the prophylactic effect of gabexate with ulanistatin was compared in two clinical trials. The results can be summarised by stating that, although there is a small risk reduction, particularly in the ulanistatin subgroup, there is no solid evidence that antiprotease drugs significantly influence the incidence of post-ERCP pancreatitis. The same conclusion can be drawn from a recently published meta-analysis (Seta & Noguchi 2011) on the basis of which it can be stated that the primary studies were not of high quality enough to come to the proper consequences. Nevertheless, protease inhibitors are costly.
\n\t\t\t\t\n\t\t\t\t\t\tNitroglycerin (glycerine trinitrate) proved to be effective in some reports, but ineffective in others. Based on two meta-analyses (Bang et al. 2009, Shao et al. 2010) of pooled data from five randomised controlled trials it can be concluded that nitroglycerin administered orally or sublingual may reduce the incidence of post-ERCP pancreatitis, but transdermal nitroglycerin is ineffective. The use of nitroglycerin is often associated with transient hypotension and headache, therefore the ESGE guideline does not recommend its routine use in the prophylaxis of post-ERCP pancreatitis (Dumonceau et al. 2010).
\n\t\t\t\t\t\n\t\t\t\t\t\tNifedipin was also tested, because calcium channel blockers have proved to be effective in the prevention of experimental pancreatitis. In clinical trials, however, nifedipin failed to show a significant effect in the prevention of post-ERCP pancreatitis (Prat et al. 2002).
\n\t\t\t\t\t\n\t\t\t\t\t\tOther drugs (lidocaine spray, epinephrine spray, Botulinum toxin injected intrapapillary) tested with the intention of reducing the sphincter of Oddi pressure failed to show any efficacy (Gorelick et al. 2004, Matsushita et al. 2009, Schwartz et al. 2004).
\n\t\t\t\tThere is only a single study evaluating the ceftazidime for prophylaxis of post-ERCP pancreatitis. This antibiotic was given in a dose of 2 g intravenously 30 min prior to the investigation and a significant reduction in the incidence of post-ERCP pancreatitis was observed (Raty et al. 2001). Further data are necessary to establish the real place of antibiotics in the prevention of ERCP-related pancreatitis.
\n\t\t\t\tThe following antioxidant agents were investigated for prevention of ERCP related pancreatitis: N-acetylcysteine (Katsinelos P. et al. 2005), beta-carotene (Lavy et al. 2004) and allopurinol. The free radical scavenger N-acetylcysteine and beta-carotene failed to show any beneficial effect. Allopurinol is a xanthine oxidase inhibitor and an antioxidant with antiapoptotic property. Four randomised clinical trials dealing with its effect in the prevention of post-ERCP hyperamylasemia and pancreatitis were published. Three of them reported negative outcomes but in two studies allopurinol proved to be effective in the reduction of the incidence of hyperamylasemia, and in one of them also in that of acute pancreatitis, particularly in patients submitted to high risk procedures (Martinez-Torres et al. 2009). Allopurinol was administered orally in a dose of 300 mg at 15 and 3 hours before ERCP.
\n\t\t\t\tSeveral agents acting by interruption of the inflammatory cascade were tested. Glucocorticoids do not reduce the incidence of post-ERCP pancreatitis according to a meta-analysis based on six randomised controlled trials (Bay et al. 2008). Similarly to glucocorticoids pentoxifylline, semapimod, and acethylhydrolase (a recombinant platelet-activating factor) all proved to be ineffective. Interleukin-10 reduced the incidence and severity of post-ERCP pancreatitis in an initial study (Deviere et al. 2001), but further trials could not confirm its effectiveness. As suggested by observational and animal studies, heparin has also an anti-inflammatory effect, inhibit the activity of pancreatic proteases and improves pancreatic circulation, but in clinical randomised controlled trials neither unfractionated heparin (Barkay et al. 2008), nor low molecular-weight heparin (Rabenstein T et al 2004) proved to be effective in the prophylaxis of post-ERCP pancreatitis.
\n\t\t\t\t\t\n\t\t\t\t\t\tNonsteroidal anti-inflammatory drugs (NSAIDs) inhibit phospholipase A2 which has an early role in the inflammatory cascade in acute pancreatitis. Inhibition of phospholipase A2 results in suppression of several important classes of proinflammatory lipids (prostaglandins, leukotriens, platelet-activating factor). Furthermore, NSAIDs inhibit neutrophyl-endothelial cell attachment. Indomethacin followed by diclofenac is the most potent NSAID with regard to phospholipase A2 inhibition. Indomethacin has shown to decrease the mortality of experimental pancreatitis in animals (Wildenhain et al 1989). Four prospective randomised controlled clinical studies have been published until now that compared rectally administered indomethacin or diclofenac vs. placebo (Murray et al. 2003, Sotoudehmanesh R et al. 2007, Montano Loza et al. 2007, Koshbaten M et al. 2008) (Fig. 5.). On the basis of three meta-analyses using the data of these studies rectally administered indomethacin and diclofenac in a dose of 100 mg proved to be effective in the decrease of incidence of post-ERCP pancreatitis (Elmunser et al. 2008, Zheng et al. 2008, Dai et al. 2009).
\n\t\t\t\t\tIncidence of post-ERCP pancreatitis: rectally administered NSAIDs versus placebo.
The reduction seems to be similar regardless of the degree of the risk (Zheng et al. 2008). Limitation of the original studies is the small number of the trials performed only in three countries. Therefore some scepticism related to the clinical efficacy of NSAIDs in the prophylaxis of post-ERCP pancreatitis exists, all the more because several agents tested before have shown promise in early single-centre studies, but the results were disappointing in larger multicentre randomised controlled trials. Furthermore it has to be mentioned that diclofenac administered intramuscularly or orally did not proved to be effective in lowering the rate of post-ERCP pancreatitis significantly (Cheon et al. 2007, Senol et al 2009). Further multicentre controlled studies are awaited for confirmation of the promising results of the foregoing trials. Nevertheless NSAIDs in a single dose are relatively safe, cheap, and easy to use. Therefore 100 mg of indomethacine or diclofenac administered rectally immediately before or after ERCP is routinely recommended. This standpoint is reflected also in the ESGE guidelines (Dumonceau et al. 2010).
\n\t\t\t\tPost-ERCP pancreatitis is an unforeseen complication but it can be predicted by measuring the serum amylase concentration at 2-4 hours after the procedure. It should be taken into account, however, that hyperamylasemia without pancreatitis following ERCP is well recognised and abdominal discomfort for some hours after ERCP due to intestinal distension by air insufflated during the investigation is a commonly occurring symptom, in particular in patients with functional gastrointestinal dysfunction. It is advisable to restrict oral intake of water for four hours and until serum amylase value is available. Serum amylase concentration less than 1.5 times the upper limit of normal value almost excludes post-ERCP pancreatitis and the patient can be discharged on the day of ERCP. For patients with four hours serum amylase levels more than twice the upper limit, with ongoing abdominal pain / tenderness or fever, fasting and parenteral fluid replacement is recommended. The same policy is advised in the presence of any risk factor of post-procedural pancreatitis at least for 24 hour after ERCP. Further management is depending on the 24 hour serum amylase level and clinical signs of pancreatitis.
\n\t\t\tFollowing factors listed below should be considered when indicating and performing ERCP.
\n\t\t\t\tBecause post-ERCP pancreatitis can be severe, life-threatening or even fatal, careful and adequate patient selection is one of the most important and the most effective preventive measures. ERCP should not be performed when the indication is not clear or the procedure is unlikely to benefit the patient. In borderline indications and when the aim of ERCP is solely diagnostic, non-invasive imaging methods, magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound should be performed first. Endoscopists should always take a risk-benefit analysis with knowledge of the identified patient related risk factors, when deciding whether to perform an ERCP.
Referral of patients at high risk for post-ERCP pancreatitis to a great volume specialist centre should be considered.
Minimal use of contrast material, avoidance of repeated attempts of pancreatic cannulation and use of guide wire to gain access or use of dual wire technique can be effective measures for prophylaxis in certain cases.
Risk related ERCP techniques should be avoided when possible.
Pharmacological prophylaxis with periprocedural rectal administration of NSAIDs (indomethacine or diclofenac) as a cheap, practical and safe method is routinely recommended.
Prophylactic placement of short 5 Fr pancreatic stent without inner flanges should be strongly considered for patients at high risk for development of post-ERCP pancreatitis.
Early screening for post-ERCP pancreatitis following the procedure and appropriate management is also important for the prevention or for reduction of the severity of ERCP-related pancreatitis.
The recommendations above are in concordance with the European Society of Gastrointestinal Endoscopy guideline (Dumonceau et al., 2010).
\n\t\t\tThe treatment of ERCP related pancreatitis is the same as that of the acute pancreatitis of other etiologies and it depends considerably on the severity of the pancreatitis. The therapy is mainly supportive including fasting, adequate correction of hypovolemia, and maintenance of optimal fluid balance, close monitoring for signs of local and systemic complications, and adequate pain control. Patients with mild pancreatitis can generally begin oral food intake in few days. The outflow of the pancreatic juice can be tried to improve with spasmolytics, nitroglycerin or theophyllin. Morphine should be avoided because this drug may produce high outflow resistance due to sphincter of Oddi spasm, but pethidine / meperidine are allowed if the patient requires it for pain relief. If the efficacy of pethidine / meperidine is insufficient, epidural anesthesia is the best choice or fentanyl can be given. In cases of severe pancreatitis early nasojejunal feeding can be crucial for the maintenance of integrity of the gut mucosal barrier, hereby preventing bacterial translocation into the systemic circulation. Translocated pathogen intestinal flora is namely one of the main sources of septic complications. Enteral feeding with appropriate energy intake has also a role in the correction of the nutritional imbalance due to the prolonged hypermetabolic state in severe acute pancreatitis. Adequate intravenous substitution is also very important, likewise early antibiotic prophylaxis in necrotizing pancreatitis – although still controversial, and effective antimicrobial treatment of the inflammatory complications. Infected pancreatic necrosis and infected pancreatic and peripancreatic fluid collections should be treated by surgery or by endoscopic or CT guided intervention. Treatment of the systemic complications has to be managed in an intensive care unit with close monitoring of the vital functions.
\n\t\tAcute pancreatitis is the most common and feared complication of ERCP. Post-ERCP pancreatitis is severe and potentially fatal in a significant proportion. The incidence rate has been little changed over the last decades despite important advances in endoscope and in accessory technology.
\n\t\t\tThe widely accepted criteria for the diagnosis of post-ERCP pancreatitis are serum amylase and/or lipase at least 3 times higher than the upper limit of normal values in 24 hours after the procedure accompanied by new pancreatic-type abdominal pain and symptoms and severe enough to require hospital stay or to extend the length of stay of already hospitalised patients, and/or CT/MRI consistent with the diagnosis of acute pancreatitis.
\n\t\t\tThe pathomechanism is not fully understood. It seems to be an inflammatory response to mechanical, hydrostatic, enzymatic, thermal, microbiological, and probably chemical insults that results from cannulation attempts and contrast material injection into the pancreatic duct.
\n\t\t\tA number of risk factors for developing pancreatitis after ERCP are known, they can categorised as patient related, procedure related, and investigator related risk factors. It is essential to identify patients at high risk to avoid unnecessary procedures or adopt protective technical or pharmacological measures. If patient related risk factors are present, first of all it is advised to consider patient’s referral to a specialist centre, or for selection of prophylactic measures. In borderline indications non-invasive imaging methods should be preferred. Out of procedure related risk factors papillary edema and sphincter spasm are the major factors in the induction of post-ERCP pancreatitis. For minimizing the risk of pancreatitis during the procedure the following measures should be kept in mind: atraumatic manipulation of the papilla, avoidance of repeated pancreatic duct cannulation and contrast injection, avoidance of balloon catheter dilatation of the intact sphincter, limited use of precut sphincterotomy and pancreatic sphincterotomy, avoiding placement of biliary stent through intact papilla, using soft-tipped guide wire to access bile duct, and using pure cut electrosurgical current.
\n\t\t\tDespite selecting patients and using protective technical measures post-ERCP pancreatitis can occur unexpectedly. Therefore prophylactic pharmacological intervention is routinely advised by means of rectal indomethacine or diclofenac immediately before or after the procedure. The administration of indomethacine and diclofenac in a single dose is safe, cheap, and easy and based on the few randomised controlled trials it seems to be effective in the decrease of the incidence of post-ERCP pancreatitis. Further randomised controlled trials are needed to prove the real efficacy of NSAIDs in the reduction of severe ERCP related pancreatitis. For high-risk ERCPs prophylactic placement of short pancreatic stent proved to be beneficial in experienced hands, therefore its use is recommended for few days in these cases.
\n\t\t\tCareful follow up, early screening for pancreatitis and appropriate management of the complication are crucial for the outcome. The treatment of post-ERCP pancreatitis itself does not differ from that of the acute pancreatitis of whatever etiology.
\n\t\tStability constant of the formation of metal complexes is used to measure interaction strength of reagents. From this process, metal ion and ligand interaction formed the two types of metal complexes; one is supramolecular complexes known as host-guest complexes [1] and the other is anion-containing complexes. In the solution it provides and calculates the required information about the concentration of metal complexes.
Solubility, light, absorption conductance, partitioning behavior, conductance, and chemical reactivity are the complex characteristics which are different from their components. It is determined by various numerical and graphical methods which calculate the equilibrium constants. This is based on or related to a quantity, and this is called the complex formation function.
During the displacement process at the time of metal complex formation, some ions disappear and form a bonding between metal ions and ligands. It may be considered due to displacement of a proton from a ligand species or ions or molecules causing a drop in the pH values of the solution [2]. Irving and Rossotti developed a technique for the calculation of stability constant, and it is called potentiometric technique.
To determine the stability constant, Bjerrum has used a very simple method, and that is metal salt solubility method. For the studies of a larger different variety of polycarboxylic acid-, oxime-, phenol-containing metal complexes, Martel and Calvin used the potentiometric technique for calculating the stability constant. Those ligands [3, 4] which are uncharged are also examined, and their stability constant calculations are determined by the limitations inherent in the ligand solubility method. The limitations of the metal salt solubility method and the result of solubility methods are compared with this. M-L, MLM, and (M3) L are some types of examples of metal-ligand bonding. One thing is common, and that is these entire types metal complexes all have one ligand.
The solubility method can only usefully be applied to studies of such complexes, and it is best applied for ML; in such types of system, only ML is formed. Jacqueline Gonzalez and his co-worker propose to explore the coordination chemistry of calcium complexes. Jacqueline and et al. followed this technique for evaluate the as partial model of the manganese-calcium cluster and spectrophotometric studies of metal complexes, i.e., they were carried calcium(II)-1,4-butanediamine in acetonitrile and calcium(II)-1,2-ethylendiamine, calcium(II)-1,3-propanediamine by them.
Spectrophotometric programming of HypSpec and received data allows the determination of the formation of solubility constants. The logarithmic values, log β110 = 5.25 for calcium(II)-1,3-propanediamine, log β110 = 4.072 for calcium(II)-1,4-butanediamine, and log β110 = 4.69 for calcium(II)-1,2-ethylendiamine, are obtained for the formation constants [5]. The structure of Cimetidine and histamine H2-receptor is a chelating agent. Syed Ahmad Tirmizi has examined Ni(II) cimetidine complex spectrophotometrically and found an absorption peak maximum of 622 nm with respect to different temperatures.
Syed Ahmad Tirmizi have been used to taken 1:2 ratio of metal and cimetidine compound for the formation of metal complex and this satisfied by molar ratio data. The data, 1.40–2.4 × 108, was calculated using the continuous variation method and stability constant at room temperature, and by using the mole ratio method, this value at 40°C was 1.24–2.4 × 108. In the formation of lead(II) metal complexes with 1-(aminomethyl) cyclohexene, Thanavelan et al. found the formation of their binary and ternary complexes. Glycine,
Using the stability constant method, these ternary complexes were found out, and using the parameters such as Δ log K and log X, these ternary complex data were compared with binary complex. The potentiometric technique at room temperature (25°C) was used in the investigation of some binary complex formations by Abdelatty Mohamed Radalla. These binary complexes are formed with 3D transition metal ions like Cu2+, Ni2+, Co2+, and Zn2+ and gallic acid’s importance as a ligand and 0.10 mol dm−3 of NaNO3. Such types of aliphatic dicarboxylic acids are very important biologically. Many acid-base characters and the nature of using metal complexes have been investigated and discussed time to time by researchers [7].
The above acids (gallic and aliphatic dicarboxylic acid) were taken to determine the acidity constants. For the purpose of determining the stability constant, binary and ternary complexes were carried in the aqueous medium using the experimental conditions as stated above. The potentiometric pH-metric titration curves are inferred for the binary complexes and ternary complexes at different ratios, and formation of ternary metal complex formation was in a stepwise manner that provided an easy way to calculate stability constants for the formation of metal complexes.
The values of Δ log K, percentage of relative stabilization (% R. S.), and log X were evaluated and discussed. Now it provides the outline about the various complex species for the formation of different solvents, and using the concentration distribution, these complexes were evaluated and discussed. The conductivity measurements have ascertained for the mode of ternary chelating complexes.
A study by Kathrina and Pekar suggests that pH plays an important role in the formation of metal complexes. When epigallocatechin gallate and gallic acid combine with copper(II) to form metal complexes, the pH changes its speculation. We have been able to determine its pH in frozen and fluid state with the help of multifrequency EPR spectroscopy [8]. With the help of this spectroscopy, it is able to detect that each polyphenol exhibits the formation of three different mononuclear species. If the pH ranges 4–8 for di- or polymeric complex of Cu(II), then it conjectures such metal complexes. It is only at alkaline pH values.
The line width in fluid solutions by molecular motion exhibits an incomplete average of the parameters of anisotropy spin Hamilton. If the complexes are different, then their rotational correlation times for this also vary. The analysis of the LyCEP anisotropy of the fluid solution spectra is performed using the parameters determined by the simulation of the rigid boundary spectra. Its result suggests that pH increases its value by affecting its molecular mass. It is a polyphenol ligand complex with copper, showing the coordination of an increasing number of its molecules or increasing participation of polyphenol dimers used as ligands in the copper coordination region.
The study by Vishenkova and his co-worker [8] provides the investigation of electrochemical properties of triphenylmethane dyes using a voltammetric method with constant-current potential sweep. Malachite green (MG) and basic fuchsin (BF) have been chosen as representatives of the triphenylmethane dyes [9]. The electrochemical behavior of MG and BF on the surface of a mercury film electrode depending on pH, the nature of background electrolyte, and scan rate of potential sweep has been investigated.
Using a voltammetric method with a constant-current potential sweep examines the electrical properties of triphenylmethane dye. In order to find out the solution of MG and BF, certain registration conditions have been prescribed for it, which have proved to be quite useful. The reduction peak for the currents of MG and BF has demonstrated that it increases linearly with respect to their concentration as 9.0 × 10−5–7.0 × 10−3 mol/dm3 for MG and 6.0 × 10−5–8.0 × 10−3 mol/dm3 for BF and correlation coefficients of these values are 0.9987 for MG and 0.9961 for BF [10].
5.0 × 10−5 and 2.0 × 10−5 mol/dm3 are the values used as the detection limit of MG and BF, respectively. Stability constants are a very useful technique whose size is huge. Due to its usefulness, it has acquired an umbrella right in the fields of chemistry, biology, and medicine. No science subject is untouched by this. Stability constants of metal complexes are widely used in the various areas like pharmaceuticals as well as biological processes, separation techniques, analytical processes, etc. In the presented chapter, we have tried to explain this in detail by focusing our attention on the applications and solutions of stability of metal complexes in solution.
Stability or formation or binding constant is the type of equilibrium constant used for the formation of metal complexes in the solution. Acutely, stability constant is applicable to measure the strength of interactions between the ligands and metal ions that are involved in complex formation in the solution [11]. A generally these 1-4 equations are expressed as the following ways:
Thus
K1, K2, K3, … Kn are the equilibrium constants and these are also called stepwise stability constants. The formation of the metal-ligand-n complex may also be expressed as equilibrium constants by the following steps:
The parameters K and β are related together, and these are expressed in the following example:
Now the numerator and denominator are multiplied together with the use of [metal-ligand] [metal-ligand2], and after the rearranging we get the following equation:
Now we expressed it as the following:
From the above relation, it is clear that the overall stability constant βn is equal to the product of the successive (i.e., stepwise) stability constants, K1, K2, K3,…Kn. This in other words means that the value of stability constants for a given complex is actually made up of a number of stepwise stability constants. The term stability is used without qualification to mean that the complex exists under a suitable condition and that it is possible to store the complex for an appreciable amount of time. The term stability is commonly used because coordination compounds are stable in one reagent but dissociate or dissolve in the presence of another regent. It is also possible that the term stability can be referred as an action of heat or light or compound. The stability of complex [13] is expressed qualitatively in terms of thermodynamic stability and kinetic stability.
In a chemical reaction, chemical equilibrium is a state in which the concentration of reactants and products does not change over time. Often this condition occurs when the speed of forward reaction becomes the same as the speed of reverse reaction. It is worth noting that the velocities of the forward and backward reaction are not zero at this stage but are equal.
If hydrogen and iodine are kept together in molecular proportions in a closed process vessel at high temperature (500°C), the following action begins:
In this activity, hydrogen iodide is formed by combining hydrogen and iodine, and the amount of hydrogen iodide increases with time. In contrast to this action, if the pure hydrogen iodide gas is heated to 500°C in the reaction, the compound is dissolved by reverse action, which causes hydrogen iodide to dissolve into hydrogen and iodine, and the ratio of these products increases over time. This is expressed in the following reaction:
For the formation of metal chelates, the thermodynamic technique provides a very significant information. Thermodynamics is a very useful technique in distinguishing between enthalpic effects and entropic effects. The bond strengths are totally effected by enthalpic effect, and this does not make any difference in the whole solution in order/disorder. Based on thermodynamics the chelate effect below can be best explained. The change of standard Gibbs free energy for equilibrium constant is response:
Where:
R = gas constant
T = absolute temperature
At 25°C,
ΔG = (− 5.708 kJ mol−1) · log β.
The enthalpy term creates free energy, i.e.,
For metal complexes, thermodynamic stability and kinetic stability are two interpretations of the stability constant in the solution. If reaction moves from reactants to products, it refers to a change in its energy as shown in the above equation. But for the reactivity, kinetic stability is responsible for this system, and this refers to ligand species [14].
Stable and unstable are thermodynamic terms, while labile and inert are kinetic terms. As a rule of thumb, those complexes which react completely within about 1 minute at 25°C are considered labile, and those complexes which take longer time than this to react are considered inert. [Ni(CN)4]2− is thermodynamically stable but kinetically inert because it rapidly exchanges ligands.
The metal complexes [Co(NH3)6]3+ and such types of other complexes are kinetically inert, but these are thermodynamically unstable. We may expect the complex to decompose in the presence of acid immediately because the complex is thermodynamically unstable. The rate is of the order of 1025 for the decomposition in acidic solution. Hence, it is thermodynamically unstable. However, nothing happens to the complex when it is kept in acidic solution for several days. While considering the stability of a complex, always the condition must be specified. Under what condition, the complex which is stable or unstable must be specified such as acidic and also basic condition, temperature, reactant, etc.
A complex may be stable with respect to a particular condition but with respect to another. In brief, a stable complex need not be inert and similarly, and an unstable complex need not be labile. It is the measure of extent of formation or transformation of complex under a given set of conditions at equilibrium [15].
Thermodynamic stability has an important role in determining the bond strength between metal ligands. Some complexes are stable, but as soon as they are introduced into aqueous solution, it is seen that these complexes have an effect on stability and fall apart. For an example, we take the [Co (SCN)4]2+ complex. The ion bond of this complex is very weak and breaks down quickly to form other compounds. But when [Fe(CN)6]3− is dissolved in water, it does not test Fe3+ by any sensitive reagent, which shows that this complex is more stable in aqueous solution. So it is indicated that thermodynamic stability deals with metal-ligand bond energy, stability constant, and other thermodynamic parameters.
This example also suggests that thermodynamic stability refers to the stability and instability of complexes. The measurement of the extent to which one type of species is converted to another species can be determined by thermodynamic stability until equilibrium is achieved. For example, tetracyanonickelate is a thermodynamically stable and kinetic labile complex. But the example of hexa-amine cobalt(III) cation is just the opposite:
Thermodynamics is used to express the difference between stability and inertia. For the stable complex, large positive free energies have been obtained from ΔG0 reaction. The ΔH0, standard enthalpy change for this reaction, is related to the equilibrium constant, βn, by the well thermodynamic equation:
For similar complexes of various ions of the same charge of a particular transition series and particular ligand, ΔS0 values would not differ substantially, and hence a change in ΔH0 value would be related to change in βn values. So the order of values of ΔH0 is also the order of the βn value.
Kinetic stability is referred to the rate of reaction between the metal ions and ligand proceeds at equilibrium or used for the formation of metal complexes. To take a decision for kinetic stability of any complexes, time is a factor which plays an important role for this. It deals between the rate of reaction and what is the mechanism of this metal complex reaction.
As we discuss above in thermodynamic stability, kinetic stability is referred for the complexes at which complex is inert or labile. The term “inert” was used by Tube for the thermally stable complex and for reactive complexes the term ‘labile’ used [16]. The naturally occurring chlorophyll is the example of polydentate ligand. This complex is extremely inert due to exchange of Mg2+ ion in the aqueous media.
The nature of central atom of metal complexes, dimension, its degree of oxidation, electronic structure of these complexes, and so many other properties of complexes are affected by the stability constant. Some of the following factors described are as follows.
In the coordination chemistry, metal complexes are formed by the interaction between metal ions and ligands. For these type of compounds, metal ions are the coordination center, and the ligand or complexing agents are oriented surrounding it. These metal ions mostly are the transition elements. For the determination of stability constant, some important characteristics of these metal complexes may be as given below.
Ligands are oriented around the central metal ions in the metal complexes. The sizes of these metal ions determine the number of ligand species that will be attached or ordinated (dative covalent) in the bond formation. If the sizes of these metal ions are increased, the stability of coordination compound defiantly decreased. Zn(II) metal ions are the central atoms in their complexes, and due to their lower size (0.74A°) as compared to Cd(II) size (0.97A°), metal ions are formed more stable.
Hence, Al3+ ion has the greatest nuclear charge, but its size is the smallest, and the ion N3− has the smallest nuclear charge, and its size is the largest [17]. Inert atoms like neon do not participate in the formation of the covalent or ionic compound, and these atoms are not included in isoelectronic series; hence, it is not easy to measure the radius of this type of atoms.
The properties of stability depend on the size of the metal ion used in the complexes and the total charge thereon. If the size of these metal ions is small and the total charge is high, then their complexes will be more stable. That is, their ratio will depend on the charge/radius. This can be demonstrated through the following reaction:
An ionic charge is the electric charge of an ion which is formed by the gain (negative charge) or loss (positive charge) of one or more electrons from an atom or group of atoms. If we talk about the stability of the coordination compounds, we find that the total charge of their central metal ions affects their stability, so when we change their charge, their stability in a range of constant can be determined by propagating of error [18]. If the charge of the central metal ion is high and the size is small, the stability of the compound is high:
In general, the most stable coordination bonds can cause smaller and highly charged rations to form more stable coordination compounds.
When an electron pair attracts a central ion toward itself, a strong stability complex is formed, and this is due to electron donation from ligand → metal ion. This donation process is increasing the bond stability of metal complexes exerted the polarizing effect on certain metal ions. Li+, Na+, Mg2+, Ca2+, Al3+, etc. are such type of metal cation which is not able to attract so strongly from a highly electronegative containing stable complexes, and these atoms are O, N, F, Au, Hg, Ag, Pd, Pt, and Pb. Such type of ligands that contains P, S, As, Br and I atom are formed stable complex because these accepts electron from M → π-bonding. Hg2+, Pb2+, Cd2+, and Bi3+ metal ions are also electronegative ions which form insoluble salts of metal sulfide which are insoluble in aqueous medium.
Volatile ligands may be lost at higher temperature. This is exemplified by the loss of water by hydrates and ammonia:
The transformation of certain coordination compounds from one to another is shown as follows:
A ligand is an ion or small molecule that binds to a metal atom (in chemistry) or to a biomolecule (in biochemistry) to form a complex, such as the iron-cyanide coordination complex Prussian blue or the iron-containing blood-protein hemoglobin. The ligands are arranged in spectrochemical series which are based on the order of their field strength. It is not possible to form the entire series by studying complexes with a single metal ion; the series has been developed by overlapping different sequences obtained from spectroscopic studies [19]. The order of common ligands according to their increasing ligand field strength is
The above spectrochemical series help us to for determination of strength of ligands. The left last ligand is as weaker ligand. These weaker ligand cannot forcible binding the 3d electron and resultant outer octahedral complexes formed. It is as-
Increasing the oxidation number the value of Δ increased.
Δ increases from top to bottom.
However, when we consider the metal ion, the following two useful trends are observed:
Δ increases with increasing oxidation number.
Δ increases down a group. For the determination of stability constant, the nature of the ligand plays an important role.
The following factors described the nature of ligands.
The size and charge are two factors that affect the production of metal complexes. The less charges and small sizes of ligands are more favorable for less stable bond formation with metal and ligand. But if this condition just opposite the product of metal and ligand will be a more stable compound. So, less nuclear charge and more size= less stable complex whereas if more nuclear charge and small in size= less stable complex. We take fluoride as an example because due to their smaller size than other halide and their highest electro negativity than the other halides formed more stable complexes. So, fluoride ion complexes are more stable than the other halides:
As compared to S2− ion, O22− ions formed more stable complexes.
It is suggested by Calvin and Wilson that the metal complexes will be more stable if the basic character or strength of ligands is higher. It means that the donating power of ligands to central metal ions is high [20].
It means that the donating power of ligands to central metal ions is high. In the case of complex formation of aliphatic diamines and aromatic diamines, the stable complex is formed by aliphatic diamines, while an unstable coordination complex is formed with aromatic diamines. So, from the above discussion, we find that the stability will be grater if the e-donation power is greater.
Thus it is clear that greater basic power of electron-donating species will form always a stable complex. NH3, CN−, and F− behaved as ligands and formed stable complexes; on the other hand, these are more basic in nature.
We know that if the concentration of coordination group is higher, these coordination compounds will exist in the water as solution. It is noted that greater coordinating tendency show the water molecules than the coordinating group which is originally present. SCN− (thiocynate) ions are present in higher concentration; with the Co2+ metal ion, it formed a blue-colored complex which is stable in state, but on dilution of water medium, a pink color is generated in place of blue, or blue color complex is destroyed by [Co(H2O)6]2+, and now if we added further SCN−, the pink color will not appear:
Now it is clear that H2O and SCN− are in competition for the formation of Co(II) metal-containing complex compound. In the case of tetra-amine cupric sulfate metal complex, ammonia acts as a donor atom or ligand. If the concentration of NH3 is lower in the reaction, copper hydroxide is formed but at higher concentration formed tetra-amine cupric sulfate as in the following reaction:
For a metal ion, chelating ligand is enhanced and affinity it and this is known as chelate effect and compared it with non-chelating and monodentate ligand or the multidentate ligand is acts as chelating agent. Ethylenediamine is a simple chelating agent (Figure 1).
Structure of ethylenediamine.
Due to the bidentate nature of ethylenediamine, it forms two bonds with metal ion or central atom. Water forms a complex with Ni(II) metal ion, but due to its monodentate nature, it is not a chelating ligand (Figures 2 and 3).
Structure of chelating configuration of ethylenediamine ligand.
Structure of chelate with three ethylenediamine ligands.
The dentate cheater of ligand provides bonding strength to the metal ion or central atom, and as the number of dentate increased, the tightness also increased. This phenomenon is known as chelating effect, whereas the formation of metal complexes with these chelating ligands is called chelation:
or
Some factors are of much importance for chelation as follows.
The sizes of the chelating ring are increased as well as the stability of metal complex decreased. According to Schwarzenbach, connecting bridges form the chelating rings. The elongated ring predominates when long bridges connect to the ligand to form a long ring. It is usually observed that an increased a chelate ring size leads to a decrease in complex stability.
He interpreted this statement. The entropy of complex will be change if the size of chelating ring is increased, i.e., second donor atom is allowed by the chelating ring. As the size of chelating ring increased, the stability should be increased with entropy effect. Four-membered ring compounds are unstable, whereas five-membered are more stable. So the chelating ring increased its size and the stability of the formed metal complexes.
The number of chelating rings also decides the stability of complexes. Non-chelating metal compounds are less stable than chelating compounds. These numbers increase the thermodynamic volume, and this is also known as an entropy term. In recent years ligands capable of occupying as many as six coordination positions on a single metal ion have been described. The studies on the formation constants of coordination compounds with these ligands have been reported. The numbers of ligand or chelating agents are affecting the stability of metal complexes so as these numbers go up and down, the stability will also vary with it.
For the Ni(II) complexes with ethylenediamine as chelating agent, its log K1 value is 7.9 and if chelating agents are trine and penten, then the log K1 values are 7.9 and 19.3, respectively. If the metal ion change Zn is used in place of Ni (II), then the values of log K1 for ethylenediamine, trine, and penten are 6.0, 12.1, and 16.2, respectively. The log βMY values of metal ions are given in Table 1.
Metal ion | log βMY (25°C, I = 0.1 M) |
---|---|
Ca2+ | 11.2 |
Cu2+ | 19.8 |
Fe3+ | 24.9 |
Metal ion vs. log βMY values.
Ni(NH3)62+ is an octahedral metal complex, and at 25 °C its log β6 value is 8.3, but Ni(ethylenediamine)32+ complex is also octahedral in geometry, with 18.4 as the value of log β6. The calculated stability value of Ni(ethylenediamine)32+ 1010 times is more stable because three rings are formed as chelating rings by ethylenediamine as compared to no such ring is formed. Ethylenediaminetetraacetate (EDTA) is a hexadentate ligand that usually formed stable metal complexes due to its chelating power.
A special effect in molecules is when the atoms occupy space. This is called steric effect. Energy is needed to bring these atoms closer to each other. These electrons run away from near atoms. There can be many ways of generating it. We know the repulsion between valence electrons as the steric effect which increases the energy of the current system [21]. Favorable or unfavorable any response is created.
For example, if the static effect is greater than that of a product in a metal complex formation process, then the static increase would favor this reaction. But if the case is opposite, the skepticism will be toward retardation.
This effect will mainly depend on the conformational states, and the minimum steric interaction theory can also be considered. The effect of secondary steric is seen on receptor binding produced by an alternative such as:
Reduced access to a critical group.
Stick barrier.
Electronic resonance substitution bond by repulsion.
Population of a conformer changes due to active shielding effect.
The macrocyclic effect is exactly like the image of the chelate effect. It means the principle of both is the same. But the macrocyclic effect suggests cyclic deformation of the ligand. Macrocyclic ligands are more tainted than chelating agents. Rather, their compounds are more stable due to their cyclically constrained constriction. It requires some entropy in the body to react with the metal ion. For example, for a tetradentate cyclic ligand, we can use heme-B which forms a metal complex using Fe+2 ions in biological systems (Figure 4).
Structure of hemoglobin is the biological complex compound which contains Fe(II) metal ion.
The n-dentate chelating agents play an important role for the formation of more stable metal complexes as compared to n-unidentate ligands. But the n-dentate macrocyclic ligand gives more stable environment in the metal complexes as compared to open-chain ligands. This change is very favorable for entropy (ΔS) and enthalpy (ΔH) change.
There are so many parameters to determination of formation constants or stability constant in solution for all types of chelating agents. These numerous parameters or techniques are refractive index, conductance, temperature, distribution coefficients, refractive index, nuclear magnetic resonance volume changes, and optical activity.
Solubility products are helpful and used for the insoluble salt that metal ions formed and complexes which are also formed by metal ions and are more soluble. The formation constant is observed in presence of donor atoms by measuring increased solubility.
To determine the solubility constant, it involves the distribution of the ligands or any complex species; metal ions are present in two immiscible solvents like water and carbon tetrachloride, benzene, etc.
In this method metal ions or ligands are present in solution and on exchanger. A solid polymers containing with positive and negative ions are ion exchange resins. These are insoluble in nature. This technique is helpful to determine the metal ions in resin phase, liquid phase, or even in radioactive metal. This method is also helpful to determine the polarizing effect of metal ions on the stability of ligands like Cu(II) and Zn(II) with amino acid complex formation.
At the equilibrium free metal and ions are present in the solution, and using the different electrometric techniques as described determines its stability constant.
This method is based upon the titration method or follows its principle. A stranded acid-base solution used as titrate and which is titrated, it may be strong base or strong acid follows as potentiometrically. The concentration of solution using 103− M does not decomposed during the reaction process, and this method is useful for protonated and nonprotonated ligands.
This is the graphic method used to determine the stability constant in producing metal complex formation by plotting a polarograph between the absences of substances and the presence of substances. During the complex formation, the presence of metal ions produced a shift in the half-wave potential in the solution.
If a complex is relatively slow to form and also decomposes at measurable rate, it is possible, in favorable situations, to determine the equilibrium constant.
This involves the study of the equilibrium constant of slow complex formation reactions. The use of tracer technique is extremely useful for determining the concentrations of dissociation products of the coordination compound.
This method is based on the study of the effect of an equilibrium concentration of some ions on the function at a definite organ of a living organism. The equilibrium concentration of the ion studied may be determined by the action of this organ in systems with complex formation.
The solution of 25 ml is adopted by preparing at the 1.0 × 10−5 M ligand or 1.0 × 10−5 M concentration and 1.0 × 10−5 M for the metal ion:
The solutions containing the metal ions were considered both at a pH sufficiently high to give almost complete complexation and at a pH value selected in order to obtain an equilibrium system of ligand and complexes.
In order to avoid modification of the spectral behavior of the ligand due to pH variations, it has been verified that the range of pH considered in all cases does not affect absorbance values. Use the collected pH values adopted for the determinations as well as selected wavelengths. The ionic strengths calculated from the composition of solutions allowed activity coefficient corrections. Absorbance values were determined at wavelengths in the range 430–700 nm, every 2 nm.
For a successive metal complex formation, use this method. If ligand is protonate and the produced complex has maximum number of donate atoms of ligands, a selective light is absorbed by this complex, while for determination of stability constant, it is just known about the composition of formed species.
Bjerrum (1941) used the method stepwise addition of the ligands to coordination sphere for the formation of complex. So, complex metal–ligand-n forms as the following steps [22]. The equilibrium constants, K1, K2, K3, … Kn are called stepwise stability constants. The formation of the complex metal-ligandn may also be expressed by the following steps and equilibrium constants.
Where:
M = central metal cation
L = monodentate ligand
N = maximum coordination number for the metal ion M for the ligand
If a complex ion is slow to reach equilibrium, it is often possible to apply the method of isotopic dilution to determine the equilibrium concentration of one or more of the species. Most often radioactive isotopes are used.
This method was extensively used by Werner and others to study metal complexes. In the case of a series of complexes of Co(III) and Pt(IV), Werner assigned the correct formulae on the basis of their molar conductance values measured in freshly prepared dilute solutions. In some cases, the conductance of the solution increased with time due to a chemical change, e.g.,
It is concluded that the information presented is very important to determine the stability constant of the ligand metal complexes. Some methods like spectrophotometric method, Bjerrum’s method, distribution method, ion exchange method, electrometric techniques, and potentiometric method have a huge contribution in quantitative analysis by easily finding the stability constants of metal complexes in aqueous solutions.
All the authors thank the Library of University of Delhi for reference books, journals, etc. which helped us a lot in reviewing the chapter.
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