Intravenous Tubing Research Articles

Reduction in Intraoperative Bacterial Contamination of Peripheral Intravenous Tubing Through the Use of a Passive Catheter Care System

Bacterial contamination of intravascular devices has been associated with increased morbidity and mortality in various hospital settings, including the perioperative environment. Catheter hub disinfection has been shown in an ex vivo model to attenuate intraoperative injection of bacterial organisms originating from the anesthesia provider's hands, providing the impetus for improvement in intraoperative disinfection techniques and compliance. In the current study, we investigated the clinical effectiveness of a new, passive catheter care station in reducing the incidence of bacterial contamination of open lumen patient IV stopcock sets. The secondary aim was to evaluate the impact of this novel intervention on the combined incidence of 30-day postoperative infections and IV catheter-associated phlebitis. Five hundred ninety-four operating room environments were randomized by a computer-generated list to receive either a novel catheter care bundle (HubScrub and DOCit) or standard caps in conjunction with a sterile, conventional open lumen 3-way stopcock set (24 inch with 3-gang 4-way and T-Connector). Patients underwent general anesthesia according to usual practice and were followed prospectively for 30 postoperative days to identify the development of health care-associated infections (HCAIs) and/or phlebitis. The primary outcome was intraoperative bacterial contamination of the primary stopcock set used by the anesthesia provider(s). The secondary outcome was the combined incidence of 30-day postoperative infections and phlebitis. Five hundred seventy-two operating rooms were included in the final analysis. Study groups were comparable with no significant differences in patient, provider, anesthetic, or procedural characteristics. The catheter care station reduced the incidence of primary stopcock lumen contamination compared with standard caps (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.63-0.98, P = 0.034) and was associated with a reduction in the combined incidence of HCAIs and IV catheter-associated phlebitis with and without adjustment for patient and procedural covariates (OR(adjusted) 0.589, 95% CI 0.353-0.984, P = 0.040). The risk-adjusted number needed to treat to eliminate 1 case of lumen contamination was 9 (95% CI 3.4-13.5) patients, whereas the risk-adjusted number needed to treat to eliminate 1 case of HCAI/catheter-associated phlebitis was 17 (95% CI 11.8-17.9) patients. Intraoperative use of a passive catheter care station significantly reduced open lumen bacterial contamination and the combined incidence of 30-day postoperative infections and phlebitis.

Assessing the Influence of Insulation on Intravenous Fluid Infusion Temperature

Inducing therapeutic hypothermia using chilled saline in resuscitated cardiac arrest patients has been shown to be feasible and effective. Limited research exists assessing the efficiency of this cooling method. The objective of this study was to assess the change in temperature of 4°C saline upon exiting an infusion set in the laboratory setting while varying conditions of fluid delivery. Efficiency was studied by assessing change in fluid temperature (°C) during the infusion under four laboratory conditions. Each condition was performed four times using 1-L bags of normal saline. Fluid was infused into a 1000-mL beaker through 10 gtt/mL tubing. Flow rate was controlled using a tubing clamp and in-line transducer with a flow meter, while temperature was continuously monitored in a side port at the terminal end of the intravenous (IV) tubing using a digital thermometer. The four conditions included different insulation methods. Descriptive statistics and analysis of variance were performed to assess changes in fluid temperature. The mean (±SD) fluid temperature at time 0 was 3.2°C (95% confidence interval [CI] = 3.0 to 3.4 °C) with no significant difference in starting temperature between groups (p = 0.45). When flow rate was constant, it was determined that fluid temperatures were significantly cooler when infused using a chilled, gel-filled sleeve around the saline bag (p < 0.006). In a laboratory setting, the most efficient method of infusing cold fluid appears to be a method that both keeps the bag of fluid insulated and infused at a faster rate.

Exposure to di(2-ethylhexyl) phthalate in premature neonates in a neonatal intensive care unit in Taiwan

Neonates are exposed to high levels of di(2ethylhexyl) phthalate through numerous medical procedures in the neonatal intensive care unit. Our aim was to assess the contribution of specific medical devices to the di(2-ethylhexyl) phthalate exposure of neonates. Prospective. University hospital. We recruited 32 premature neonates, 20 with very low birth weight (<1500 g) and 12 with low birth weight (<2500 g), and 31 controls at a neonatal intensive care unit from a medical center in central Taiwan. Interventions were based on a clinical need and used standard materials and devices, including endotracheal tubes, continuous positive airway pressure, oxygen hood, intravenous injection, intralipid injection, blood transfusion, orogastric tubes, nasogastric tubes, umbilical venous catheterization, umbilical arterial catheterization, chest tube, and isolate. We recorded the medical procedures of each subject, collected their urine samples, and determined the urinary concentration of three metabolites of di(2-ethylhexyl) phthalate using reversed-phase high-performance liquid chromatography-atmospheric pressure chemical ionization-tandem mass spectrometry. Median levels of di(2-ethylhexyl) phthalate metabolites in premature neonates treated with an endotracheal tube and orogastric tube or nasogastric tube were significantly higher than those not treated with an endotracheal tube, orogastric tube, or nasogastric tube. Median levels of di(2-ethylhexyl) phthalate metabolites in premature neonates treated with intravenous injection were ≥ 2-fold higher than those of healthy controls who received intravenous injections (p = .01). Median levels of three di(2-ethylhexyl) phthalate metabolites were similar in very-low-birth-weight and low-birth-weight neonates. These data suggest that polyvinyl chloride-containing devices are the major defining factor in di(2-ethylhexyl) phthalate exposure levels in neonates in the neonatal intensive care unit. We urge the use of polyvinyl chloride-free or alternative materials in medical devices, especially for endotracheal tubes, orogastric tubes, nasogastric tubes, and intravenous tubing in the neonatal intensive care unit. The health effects of high di(2-ethylhexyl) phthalate exposure on premature neonates in the neonatal intensive care unit is worthy of further investigation.

Avoiding Inadvertent Intravenous Injection of Oral Liquids; Medication within Intravenous Tubing may be Overlooked; Searching by Drug Name Gives Information on Wrong Drug

These medication errors have occurred in health care facilities at least once. They will happen again—perhaps where you work. Through education and alertness of personnel and procedural safeguards, they can be avoided. You should consider publishing accounts of errors in your newsletters and/or presenting them at your inservice training programs. Your assistance is required to continue this feature. The reports described here were received through the Institute for Safe Medication Practices (ISMP) Medication Errors Reporting Program. Any reports published by ISMP will be anonymous. Comments are also invited; the writers' names will be published if desired. ISMP may be contacted at the address shown below. Errors, close calls, or hazardous conditions may be reported directly to ISMP through the ISMP Web site ( www.ismp.org ), by calling 800-FAIL-SAFE, or via e-mail at ismpinfo@ismp.org . ISMP guarantees the confidentiality and security of the information received and respects reporters' wishes as to the level of detail included in publications.

Avoiding Subarachnoid or Intravascular Injection of Local Anesthetics

Avoiding Subarachnoid or Intravascular Injection of Local Anesthetics

1809 Reduced Duration of CPAP in Preterm Babies Receiving Kangaroo Care within an Hour of Birth - Randomized Trial

Background and AimsKangaroo Mother Care (KMC) is conventionally initiated in a baby who is otherwise stable but may still be on intravenous fluids, tube feeding and/or oxygen. We hypothesized that...

The Effect of Tubing Dwell Time on Insulin Adsorption During Intravenous Insulin Infusions

Insulin adsorbs to plastic tubing, which decreases the concentration of an insulin solution delivered from an intravenous infusion set. Dwelling insulin within tubing before starting the infusion decreases adsorption but delays treatment initiation and wastes time in infusion preparation. The lack of data on dwell time effects results in wide variability in practice. We aim to determine the effect of dwell time on insulin concentration from intravenous infusion tubing. In this in vitro study, we used insulin solutions with concentrations of 0.1 unit/mL, 1 unit/mL, and 10 units/mL. Each solution dwelled in intravenous infusion sets for 0, 15, 30, or 60 min. After the dwell, we measured insulin concentrations from the solution bags and tubing. We repeated each insulin concentration-dwell time combination five times. Comparisons were performed using analyses of variance. For each of the three insulin concentrations, the mean insulin concentrations from the tubing were not significantly different between dwell times. Duration of dwell time did not affect insulin adsorption in polypropylene intravenous infusion sets. We recommend that following a 20-mL flush, insulin infusions can be started without any dwell time. Removal of dwell times may improve clinical practice by minimizing preparation time and will allow faster initiation of insulin infusion therapy.

The Kebab Technique

Patellar fractures not amenable to reconstruction are managed by either partial or complete patellectomy. The reconstitution of the extensor mechanism in the former entails secure fixation of the patellar tendon to the bony remnant. Usually this is done by fixation of the tendon to the patellar remnant by passing sutures from the tendon through the bone and tying these at the proximal pole. The passage of these sutures is many a times vexing and takes up a lot of the operating time as the drill holes usually entrap the needles or the suture comes out at a less than optimal position, or the holes need to be enlarged considerably to enable easy passage, which creates large holes acting as stress risers in the patella. We present an easy technique wherein the suture passage through the bone is done through an intravenous cannula tubing. The procedure is rapid and easy, with accurate placement of the sutures and minimal damage to the bony remnant. The only additional equipment used is an angiocath and no specialized needles or drill bits have to be used.

Maximum Flow Rates Achievable Through Peripherally Inserted Central Catheters Using Standard Hospital Infusion Pumps

PurposeTo determine maximum flow rates through peripherally inserted central catheters (PICCs) using a standard hospital infusion pump. BackgroundTwo questions asked with the use of PICCs and flow rates are (1) can a PICC be used to give nonemergent fluid boluses, and (2) can standard hospital infusion pumps develop enough pressure to rupture a catheter? MethodsNew PICCs of different brands and gauges were gathered. Six standard hospital infusion pumps and tubing of the same brand and model were used. The pressure sensor was set at 600 mm Hg. The pumps were connected through the access ports of each intravenous tube in a series fashion. The PICC end was submerged under 5 cm of water. All equipment and fluids were at 70°F. PICCs were trimmed to 45 cm. Fluids were run starting with the first pump at 999 mL/hour and then additional pumps were added until the pump's 600 mm Hg limit stopped the infusion or catheter rupture. Tests with the same PICC were repeated and recorded. ResultsFlow rates varied with the type, size, gauge, and brand of PICC catheter. Flows were achieved from 2,100 mL/hour to >6,000 mL/hour. None of the PICCs ruptured. ConclusionsMaximum flow rates through PICCs were limited by the maximum pressure allowed by the standard hospital infusion pump. A standard hospital infusion pump cannot generate enough pressure to rupture a new-out-of-the-package catheter. Implication for PracticeNonemergent fluid boluses can be given through PICCs and standard infusion pumps will not rupture a PICC.

3 Tesla turbo‐FLASH magnetic resonance imaging of deglutition

In this article we describe a methodology for obtaining high-quality dynamic magnetic resonance imaging (MRI) sequences of the swallow sequence in healthy volunteers. The study includes comparison to previous work done in our lab using a 1.5 Tesla (T) magnet. Case series. Three healthy volunteers underwent turbo-fast low angle shot MRI at 3T while swallowing liquid boluses delivered via intravenous tubing to the oral cavity. Imaging was performed in the sagittal and axial planes. Imaging provided by this sequence provided high temporal resolution, with the ability to depict deglutition in the axial and sagittal planes. Comparison with imaging at 1.5 T demonstrated benefits in temporal resolution and signal-to-noise. Anatomic information provided differed from comparative videofluoroscopy. MRI of swallowing using the described technique is reliable and provides a unique evaluation of the swallowing sequence.

Simulating Laparoscopic Renal Hilar Vessel Injuries: Preliminary Evaluation of a Novel Surgical Training Model for Residents

Many surgical training programs utilize simulation-based strategies for instruction and assessment of laparoscopic skills. While the use of inanimate, animate, and virtual-reality simulation for basic or procedural skills training has been well described, the use of simulation for the purpose of training surgeons in managing intraoperative laparoscopic complications has been given less attention. We describe a novel, affordable inanimate surgical model for use in simulation-based training of laparoscopic renal hilar vessel injury management. Using a laparoscopic box trainer, a half-inch Penrose drain, standard silicone intravenous tubing, and a commercially available kidney part-task trainer, an inanimate surgical training model was developed to simulate various clinical scenarios involving renal hilar vessel injuries. To evaluate the construct validity of this training model, urology residents from the University of California, Irvine, completed a simulated scenario involving a renal vein injury (RVI) during laparoscopic radical nephrectomy (LRN). This surgical model is able to simulate both renal arterial and venous injuries during laparoscopic radical and partial nephrectomy scenarios. Initial cost to construct the model was ~800 U.S. dollars (USD) and each subsequent use was an additional 7 USD. Resident training level correlated strongly with technical performance (p<0.01) and "blood loss" (p=0.02) during the "RVI during LRN" scenario. The checklist and global rating scale used to assess performance demonstrated adequate reliability (Cronbach's α=0.82). While further validation, technical refinement, and improved fidelity are being considered, we present a novel, affordable surgical model for simulating laparoscopic renal hilar vessel injuries that is suitable for urology trainees.

The Reliability of Measurement of Tissue Pressure in Compartment Syndrome

Although there is general agreement as to the pathophysiology and treatment of compartment syndrome and the importance of intramuscular pressure measurements, there are many methods described to obtain these measurements. Variations in experimental measurements using current electronic monitoring, needle, and catheter devices of 18 to 22 mmHg are reported and are enough to cause errors in clinical decision-making that could result in significant clinical consequences. Current unacceptable reliability has been reported with the use of bevel-tipped needles and the clinical Whitesides technique. Because this is contrary to the authors' cumulative clinical and research experience with various methods when properly used (with the small required saline flush to assure a fluid continuum between tissue and the pressure monitor), this study was designed to clarify these problems. Although the two Whitesides techniques (original and clinical) are not in current use where digital methods are available, the clinical method is still used in the Third World. To eliminate comparative errors, a laboratory compartment syndrome model was devised to allow simultaneous testing of different devices in the same area of fusiform muscle against increasing intramuscular pressure using the same transducer and monitor. Slit catheters, side-ported bevel-tipped needles, and 18-gauge bevel-tipped needles were compared against each other. The two Whitesides methods using a capillary meniscus and a mercury manometer were compared against a current electronic transducer method using identical 18-gauge bevel-tipped needles and varying diameter capillary tubing. The side-ported needle, slit catheter, and 18-gauge bevel-tipped needle were found to measure equivalent pressure when compared statistically with each other in pairs. The original Whitesides method using a 1.25-mm capillary tube and the digital transducer method using 18-gauge bevel-tipped needles was also found to measure equivalent pressure. The clinical Whitesides method using current plastic intravenous tubing of 3.0-mm internal diameter fails to produce an obvious capillary meniscus, leading to diminished reliability in the measured pressure. The slit catheter, side-ported bevel-tipped needle, or an 18-gauge needle, when appropriately used with current electronic transducer monitoring, may be used clinically with confidence. When digital methods are not available, the original Whitesides method using 1.25-mm glass capillary tubing is an accurate alternative but requires preplanning. When only 3-mm tubing is available, this method is relatively useful when electronic means are not available by averaging several consecutive measurements.

DI (2-ETHYLHEXYL) PHTHALATE EXPOSURE DURING CATHETERIZATION

Background and Aims: Diethylhexyl phthalate (DEHP) may produce potential toxicity in human bodies. Medical devices containing DEHP are widely used in patients undergoing catheterization, but data on catheterization exposures are limited. In this prospective study, we will investigate the difference of DEHP level before and after catheterization. Methods: A total of 16 patients (M/F 12/4, mean age 15.7±10.4 years) with congenital heart disease who underwent catheterization were enrolled. Urine samples were collected on admission, pre-catheterization, post-catheterization, and discharge times for assessment of urinary DEHP. We measured mono-(2-ethylhexyl) phthalate (MEHP) and two oxidative DEHP metabolites, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP). Exposures to DEHP, such as plastic container, catheters, and intravenous tubing systems were recorded. Results: Distribution of creatinine-adjusted phthalate metabolites is shown in Table 1. There were significant differences between admission and pre-catheterization times in terms of MEHP (p=0.01), MEHHP (p=0.005), and MEOHP (p=0.001). There were significant differences between pre-catheterization and post-catheterization times in terms of MEHP (p=0.004), MEHHP (p=0.003), and MEOHP (p=0.002). There were no significant differences between post-catheterization and discharge times in terms of MEHP, MEHHP, and MEOHP. There were significant differences between admission and discharge times in terms of MEHHP (p=0.01), and MEOHP (p=0.005) except MEHP. DEHP metabolites on four different times were not significantly associated with PVC-containing systems except MEHHP on discharge (r=-0.564, p &lt; 0.05). After a multivariate logistic regression, MEHHP levels were associated with intravenous tubing systems (p=0.07). Conclusions: Use of intravenous tubing systems in catheterization may result in higher exposure to DEHP as reflected by elevated urinary levels of MEHP.

Bedeutung von Rückschlagventilen

Radke OC, Werth K, Borg-von-Zeppelin M et al. Two serial check valves can prevent cross-contamination through intravenous tubing during total intravenous anesthesia. Anesth Analg 2010; 111: 925 – 928

Non-return valves do not prevent backflow and bacterial contamination of intravenous infusions

Non-return valves (NRVs) are designed to avoid backflow of infusion fluid against the designated direction of flow (DDF) when more than one infusion is delivered via one venous access. We tested in vitro whether NRVs reliably prevent flow against the DDF at clinically relevant low flow rates. Since catheter-related infections caused by the infusion of contaminated fluids represent a relevant problem in patient care, we tested whether NRVs preclude bacterial contamination of infusions proximal to the NRVs and thus might play a role in preventing healthcare-associated infections. Additionally, the incidence of bacterial contamination of drips and infusion fluids in our intensive care unit (ICU) was quantified. In vitro, a low flow against the DDF of ten examples each of five different NRV models was applied and the integrity for fluid and transmigration of three different indicator micro-organisms was tested. Second, we investigated whether contamination of intravenous infusion tubing collected from patients treated on our ICU occurred. Largely independent from the model, 40% of the tested NRVs were not leak-tight for fluids when a pressure against the DDF was built up slowly. In 30%, bacteria migrated against the DDF and were detected proximal to the valve. In 6.7% of the tubing samples collected from ICU patients we detected bacterial contamination. In conclusion, contamination of drips is a relevant problem on ICU. NRVs neither reliably prevent backflow of fluids nor serve as micro-organism filters. Therefore they cannot be recommended as a way of reducing healthcare-associated infections.

Stability of thyroid hormones during continuous infusion

We investigated the stability of thyroid hormones during a mode of continuous drug infusion via polypropylene tubing using the same conditions that would be applied to treating patients in a hospital setting. The diluted thyroid hormones were prepared using aseptic technique, stored at 2-8°C (36-46°F) and tested within 24 h of preparation for stability and percent recovery from within plastic tubing. Experiments were done in duplicate with triplicate sets of readings for each assay point. Only T(4) prepared with 5% dextrose water (D5W) containing 1 mg/mL albumin remained constant, stable, predictable and accurate over time under various conditions. Other methods of preparation lost drug by adhering to the plastic containers and tubing by as much as 40% of starting concentration. T(3) recovery in the presence of 1 mg/mL of albumin was 107±2% (mean±standard error of the mean) of anticipated drug concentrations. We conclude from this series of experiments that to maintain an accurate and stable dosing of patients receiving intravenous thyroid hormones, 1 mg/mL of albumin must be added to the infusate to prevent lost on the plastic intravenous tubing.

Impact of a Comprehensive Safety Initiative on Patient-controlled Analgesia Errors

Adverse drug events related to patient-controlled analgesia (PCA) place patients at risk. We reviewed all critical incident reports at three tertiary care hospitals dated January 1, 2002, to February 28, 2009. In this longitudinal cohort study, critical incidents attributable to PCA errors were identified, and each incident was investigated. A safety intervention was implemented in February 2006 and involved new PCA pumps, new preprinted physician orders, nursing and patient education, a manual independent double-check, and a formal nursing transfer of accountability. A total of 25,198 patients were treated with PCA during this study, and 62 errors were found (0.25%), with 21 (0.08%) involving pump programming. All errors occurred before the safety interventions were put in place. Compared with the preintervention period, the odds ratio of a PCA error postintervention was 0.28 (95% CI = 0.14, 0.53; P < 0.001) whereas the odds ratio of a pump-programming error postintervention was 0.05 (95% CI = 0.001, 0.30; P < 0.001). Programming the wrong drug concentration was the most common programming error (10 of 21). Improper setup of intravenous tubing was also common (8 of 62), with one incident leading to respiratory arrest. Most PCA errors resulted in no harm, but there was negative impact to patients 34% of the time. At less than 1%, the incidence of PCA errors is relatively low. Most errors occur during PCA administration. Safety can be improved by addressing equipment, education, and process issues.

Two Serial Check Valves Can Prevent Cross-Contamination Through Intravenous Tubing During Total Intravenous Anesthesia

Nonsterile handling of propofol for anesthesia has been linked with severe sepsis and death. Placing a single check valve in the IV tubing does not prevent retrograde ascension of pathogens into propofol-filled syringes, so we designed an IV tubing set with multiple check valves. To estimate the efficacy of this design, we measured the concentration of pathogens detected upstream in the IV tubing in relation to the pathogen concentration in a model of a contaminated patient. A glass container with a rubber sealed port was filled with a suspension of either bacteria or phagocytes and kept at 37°C ("contaminated patient" model). A bag of normal saline was connected to an IV cannula, punctured through the rubber sealed port of the patient model. Two additional sidestream infusion lines were connected to syringes in 2 standard infusion pumps. One of the syringes contained propofol and the other contained normal saline as a substitute for an opioid preparation. After 5 hours of infusion, we obtained samples from different parts of the infusion lines and syringes. The samples were streaked out on blood agar plates and incubated at 37°C for 24 hours. We repeated this experiment with 6 different pathogens. We incubated 825 agar plates. Whereas the concentration of bacteria and phagocytes in the "patient" had significantly increased during the 5-hour experiments (positive control), no bacterial growth could be detected in any of the incubated plates. The data from this experimental setting suggest that the design with multiple check valves in paired configuration prevents retrograde contamination. Of note, this does not permit the reuse of propofol syringes because reusing is against the manufacturer's recommendations.

Stopcock lumen contamination does not reflect the full burden of bacterial intravenous tubing contamination: Analysis using a novel injection port

Prior clinical studies have used injection port lumen culture as a marker of intravenous (IV) fluid system contamination. We hypothesized that culturing injected saline (effluent) is a more sensitive method of detecting IV fluid system bacterial contamination than lumen culture. To test this hypothesis, we compared the incidence of lumen contamination with effluent contamination in a simulated setting. We also measured the effect of a novel injection port protective device (Port Guide; Matrix Tooling, Inc, Wood Dale, IL) on contamination. In this ex vivo study, 33 providers performed 5 injections of 1 mL sterile saline into each of 4 injection port designs: (1)stopcock, (2) stopcock with Port Guide, (3) stopcock with disinfectable needleless closed connector (DNCC), and (4) stopcock with DNCC and Port Guide. The primary outcome was the rate of effluent contamination with simultaneously contaminated injection port lumen. Bacterial organisms were recovered from the effluent in 17 of the 132 injection ports evaluated. Of those 17 injection ports with contaminated effluent, 4 injection port lumens were simultaneously contaminated (24%). Additionally, use of the stopcock with Port Guide significantly reduced effluent contamination. Effluent culture is a more sensitive marker of IV fluid system contamination than injection port lumen culture. A novel protective device on the stopcock (Port Guide) significantly reduced IV fluid system bacterial contamination.

Potential inaccurate quantitation and sizing of protein aggregates by size exclusion chromatography: Essential need to use orthogonal methods to assure the quality of therapeutic protein products

The levels, types, and sizes of aggregates in therapeutic protein products are important quality attributes that have received considerable attention from the biotechnology industry and regulatory agencies. 1 Rosenberg A.S. Effects of protein aggregates: An immunologic perspective. AAPS J. 2006; 8: E501-E507 Crossref PubMed Scopus (1080) Google Scholar , 2 Cordoba‐Rodriguez R. Aggregates in MAbs and recombinant therapeutic proteins: A regulatory perspective. BioPharm Int. 2008; 21: 44-53 Google Scholar In the context of therapeutic proteins, the term “aggregates” typically refers to assemblies of protein molecules that are considered degradation products and can include a range of sizes (from dimers to visible particles) and types (e.g., covalently crosslinked or noncovalent). Aggregation can occur at all steps in the manufacturing process, during product shipping and storage and even during administration to the patient (e.g., due to interactions with intravenous tubing). 3 Chi E.Y. Krishnan S. Randolph T.W. Carpenter J.F. Physical stability of proteins in aqueous solution: Mechanism and driving forces in nonnative protein aggregation. Pharm Res. 2003; 20: 1325-1336 Crossref PubMed Scopus (1098) Google Scholar , 4 Cromwell M.E. Hilario E. Jacobson F. Protein aggregation and bioprocessing. AAPS J. 2006; 8: E572-E579 Crossref PubMed Scopus (615) Google Scholar Moreover, aggregates of therapeutic proteins may cause adverse effects in patients such as injection site reactions, anaphylaxis, and immunogenicity, with consequences ranging from patient discomfort to permanent harm and potentially death. 5 Kessler M. Goldsmith D. Schellekens H. Immunogenicity of biopharmaceuticals. Nephrol Dial Transplant. 2006; 21: 9-12 Crossref PubMed Scopus (174) Google Scholar , 6 Hooks W.K. Urgent inhibitor issues: Targets for expanded research. Haemophilia. 2006; 12: 107-113 PubMed Google Scholar , 7 Reipert B.M. van den Helden P.M. Schwartz H.‐.P. Hausl C. Mechanisms of action of immune tolerance induction against factor VIII in patients with cogenital haemophilia A and factor VIII inhibitors. Br J Haemophilia. 2007; 136: 12-25 Crossref PubMed Scopus (82) Google Scholar , 8 Hermeling S. Crommelin D.J. Schellekens H. Jiskoot W. Structure‐immunogenicity relationships of therapeutic proteins. Pharm Res. 2004; 21: 897-903 Crossref PubMed Scopus (498) Google Scholar Importantly, the amount, type, size and other characteristics (e.g., the conformation of protein molecules within the aggregate) of aggregates needed to induce adverse effects cannot be predicted for a given product. It is thought, however, that even trace amounts (e.g., <1% by mass) of certain aggregates might be responsible for adverse effects in patients, and that larger‐sized aggregates are more prone to induce immunogenicity than smaller oligomers. 1 Rosenberg A.S. Effects of protein aggregates: An immunologic perspective. AAPS J. 2006; 8: E501-E507 Crossref PubMed Scopus (1080) Google Scholar , 9 Fradkin A.H. Carpenter J.F. Randolph T.W. Immunogenicity of aggregates of recombinant human growth hormone in mouse models. J Pharm Sci. 2009; 98: 3247-3264 Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar Therefore, tremendous effort is put into minimizing protein aggregation during manufacturing steps and in the final formulation/dosage form.