Unveiling the hidden clinical and economic impact of preanalytical errors

Introduction

The preanalytical phase is the main basis upon which the following steps of the testing process depend [1]. Without a thorough understanding of preanalytical complexities and challenges, the quality of laboratory work can be ultimately compromised, not only impairing the accuracy of test results but also patient care.

Despite many technological advancements in laboratory medicine, errors still occur with a relatively high frequency in daily routine. When examining the literature published over the past decades, it is quite clear that the vast majority of errors consistently occur during the preanalytical phase. Several studies have shown that the frequency of preanalytical errors can range from 30 % to over 70 % of all laboratory mistakes [2]. These figures define preanalytical errors as an important source of concern in laboratory medicine, making them the first area that requires focus and improvement. However, it is also evident that this critical issue is frequently underestimated or even completely overlooked by many clinicians and, unfortunately, by some laboratory professionals as well.

There is often a narrow focus on analytical errors, which represent only the tip of the iceberg when it comes to the broader issue of diagnostic mistakes. In reality, when we analyze the risk of diagnostic errors in laboratory medicine, evidence reveals that laboratory medicine services are directly responsible for a minority of diagnostic errors, around 10 %, while the remaining 90 % tend to occur outside the laboratory environment [3]. Although this aspect highlights the need for a broader view of healthcare quality, it does not diminish the responsibility that laboratory professionals have in addressing and minimizing extra-laboratory vulnerability, assuming the central role of training and supporting other healthcare providers for improving patient safety.

The laboratory medicine scenario

Before exploring specific issues related to the preanalytical phase, it is important to briefly revisit the scenario of the total testing process, as originally conceptualized by George Lundberg in the early 80s [4]. Lundberg’s model portrays the total testing process as a continuous loop, beginning with the clinical question process within the physician’s brain and ultimately returning to the same point after passing through the preanalytical, analytical, and post-analytical phases. This cyclical nature of activities in laboratory medicine emphasizes the critical role that each phase plays in the overall diagnostic journey. The preanalytical phase, as is commonly defined, encompasses a series of crucial activities that begin with test ordering and continue through to sample preparation before testing [1]. This phase is essential for ensuring accuracy and reliability within the entire diagnostic process. Nonetheless, it is also important to acknowledge that errors can occur at any stage throughout the testing loop, and while the frequency of these errors may vary, they have the potential to impact the quality of test results across the entire diagnostic process. Understanding this continuous cycle and the opportunities for errors is essential for improving the overall diagnostic accuracy and patient care [5].

When we consider laboratory errors in comparison to other diagnostic specialties such as radiology, pathology, and echography, there is often a tendency to think that laboratory professionals may be responsible for a disproportionately high number of mistakes. This perception leads to the assumption that laboratory performance may be worse than that of colleagues in other diagnostic fields. However, this misconception arises when errors are considered in absolute terms rather than as a rate of the volume of total tests. When we shift our focus to diagnostic errors as a percentage of all the tests performed, the situation becomes clearer and more favorable. As clearly demonstrated by several studies, the error rate in laboratory medicine is approximately 10-fold lower than that of radiology and pathology [6]. In fact, when considering safety standards, laboratory medicine proves to be even safer than other industrial sectors, such as air travel. The likelihood of losing luggage at a major airport, for example, is twice as high as the risk of an error occurring in laboratory medicine. This comparison highlights the relative safety and accuracy of laboratory work when assessed in the appropriate context [6].

Preanalytical errors and their consequences

The potential consequences of preanalytical errors in healthcare are of paramount importance, as they can significantly impact patient outcomes and healthcare systems as a whole. These consequences can be broadly categorized into two main domains: clinical and economic. From a clinical perspective, preanalytical errors can lead to inaccurate or delayed diagnoses, which can ultimately misguide treatment decisions and patient care. In some cases, this can result in worsened health outcomes, unnecessary (invasive) procedures, or even direct harm to the patient. On the other hand, from an economic standpoint, preanalytical errors contribute to raising healthcare costs, as they often require sample redraw, repeated testing, extended hospital stays, or additional treatments to correct the issues caused by these errors. Both dimensions underscore the critical need for robust preanalytical processes to ensure the best possible care for patients, while also maintaining the financial sustainability of healthcare institutions. A third, often overlooked, aspect concerns the relational challenges that preanalytical errors may cause. Due to the evidence that these errors typically occur before samples reach the laboratory, subsequent disputes over erroneous test results between laboratory personnel and clinical staff can further strain interprofessional relationships.

Summary of practical implications attributable to preanalytical errors

To summarize the impact of preanalytical errors, it is important to highlight their profound clinical and financial consequences. Preanalytical errors have been estimated to contribute to adverse clinical outcomes in approximately 15–25 % of cases. This statistic underscores the pervasive nature of these errors and their potential to undermine diagnostic accuracy, delay treatment, and affect patient safety. From a financial perspective, preanalytical errors account for approximately 0.15 % of all hospital costs. While this percentage may initially appear modest, it represents a significant financial burden when scaled to the vast operations of healthcare institutions. Within the specific context of blood collection, these errors contribute between 2 and 7 % of the total costs associated with phlebotomy. In short stay units (e.g., emergency departments and intensive care units), where rapid and accurate blood sampling is crucial, the proportion is even higher, since preanalytical errors are estimated to account for nearly one-quarter of all blood drawing costs (Figure 1). These figures highlight not only the direct costs of re-collecting and re-testing samples, but also the indirect costs, such as delays in diagnosis, extended hospital stays, and potential litigation arising from diagnostic inaccuracies. As such, addressing preanalytical errors is not merely a matter of quality improvement, but also a critical component of cost containment and efficient resource allocation within healthcare systems.

Figure 1:

Estimated cost of preanalytical errors.

Classification of errors

When analyzing the preanalytical phase, it is crucial to acknowledge that errors during this stage are not only common, but also have the potential to significantly compromise the accuracy and reliability of test results. These errors can be categorized based on where they occur within the preanalytical workflow, and each category brings unique challenges that need to be carefully managed [1] (Table 1). To begin with, patient preparation is a foundational aspect of the preanalytical phase. Variability at this stage can arise for biological factors, both within an individual and between individuals. This variability might include adequate hydration, fasting status, physical activity, or even hormonal and circadian cycles [1]. Furthermore, environmental conditions such as climate and pollution play an often-underestimated role. For instance, extreme heat can lead to dehydration, which may alter blood composition [1]. Postural changes also need to be considered because blood composition differs depending on whether the patient is in a sitting, standing, or lying position during blood collection [13]. Drawing blood from a supine patient, for example, may yield different analyte concentrations compared to a sample collected from a patient who has been standing for a prolonged period. All of these factors need to be standardized as much as possible to ensure meaningful and reliable test results. Sample collection is another critical element of the preanalytical phase, which is universally considered the cornerstone of preanalytical quality. Errors here can have a profound impact on test results. Appropriate patient identification is non-negotiable; a mislabeled tube or a case of mistaken identity can lead to erroneous diagnostic conclusions and even inappropriate care [14]. The devices used for blood collection, such as straight needles, butterfly sets, or cannulas, must be chosen carefully, as their design and gauge can affect sample quality [15]. The duration of tourniquet application is another factor of paramount importance; keeping the tourniquet in place for too long, beyond 2 min, can cause hemoconcentration, skewing the levels of certain analytes, especially those of larger and non-diffusive molecules [16]. Similarly, the type of container used for collecting blood requires careful attention, as different containers may contain additives that require an accurate (i.e., fixed) blood-to-additive ratio. For example, sodium citrate blood tubes that are typically used for performing coagulation tests must be filled to a specific volume to prevent errors in test results arising from an excess (when blood tubes are underfilled) anticoagulant concentration, which may ultimately prolong clotting times for excessive calcium sequestration [17]. The sequence in which blood tubes are drawn, known as the “order of draw”, may also be critical for preventing cross-contamination between tubes containing different types of additives [18].

The phlebotomy technique also plays a key role in this stage, as no two phlebotomists are identical in their approach [19]. Differences in experience, precision and patient interaction can lead to variability in sample quality and patient discomfort. Finally, even after blood is drawn, tubes must be appropriately mixed, with gentle inversions to ensure that the additives adequately blend with blood. Excessive sample shaking, however, must be avoided to prevent hemolysis, which can make the specimen unsuitable for testing [20]. Sample transportation to the laboratory introduces another set of challenges [21]. The time taken for transportation is critical because important delays can lead to consumption (e.g., glucose) or degradation (e.g., bilirubin) of some analytes, or release of several compounds (e.g., potassium) from the intracellular compartment. Environmental conditions such as extreme heat or cold also affect sample integrity [22]. Mishandling during transport may cause trauma to the specimen, potentially leading to blood cell injury. To mitigate these risks, validated systems, such as certified transport boxes or pneumatic tube systems, are often used to maintain consistent handling and ensure that the samples arrive in optimal condition within many healthcare facilities [23]. Once the sample reaches the laboratory, preparation for analysis becomes the next critical step. Centrifugation, a routine yet crucial process, must be standardized in terms of speed, duration, brake force, and temperature to ensure consistent results [24]. Errors during centrifugation can result in incomplete separation of plasma or serum, directly affecting downstream analyses. Aliquoting, where a portion of sample is transferred to secondary containers, is also vulnerable to errors. Mistakes such as pipetting inaccuracies, cross-contamination, or incorrect labeling of secondary tubes with the wrong patient ID can introduce significant bias into the final test results [25].

A final category of preanalytical issues pertains to sample storage. Samples must be stored under appropriate conditions to preserve their integrity. The duration of storage and the temperature at which samples are kept are key determinants of their stability. For example, prolonged storage at room temperature can lead to degradation of some analytes, while improper freezing conditions can lead to protein denaturation or nucleic acid degradation [26]. Repeated freeze-thaw cycles are particularly problematic, as they can compromise the structural integrity of a vasta array of biomolecules, affecting test outcomes [27]. Therefore, the preanalytical phase encompasses a series of interdependent steps that demand attention to detail and strict adherence to standardized protocols. From patient preparation to sample storage, each stage holds the potential to introduce variability that can undermine the reliability of test results.

The cumulative risk of sample rejection has been effectively summarized in several studies, providing an overview of the most common reasons for the inability to process specimens. Among these, hemolyzed samples represent the predominant cause, accounting for the vast majority of sample rejections [28] (Table 2). In fact, hemolysis occurs approximately four times more frequently than the second most common preanalytical issue, which is insufficient sample volume. Additionally, hemolyzed samples are rejected far more often than those that arrive in the wrong container or those that are improperly clotted. This highlights the critical need for improved handling and sample preparation to reduce the risk of these errors, which can significantly impact the efficiency of laboratory operations and the accuracy of diagnostic results.

Optimizing blood collection

The blood drawing procedure is universally recognized as the most critical step in the preanalytical phase, and for several practical reasons [29]. It is undoubtedly the activity where the highest number of problems occur, often due to errors in technique and/or incorrect actions.

One important aspect is that, while phlebotomists can be trained to follow best practices, there is also an innate skill involved in performing this procedure effectively. Some phlebotomists seem to have an inherent ability that makes them more adept at their work and can skillfully draw blood from even the most challenging sites, while others may struggle even with patients with good veins. However, beyond this natural skill heterogeneity, it is essential to acknowledge that following a well-established set of harmonized procedures can significantly improve the outcomes of blood collection. To support this, a specific document entitled “Joint EFLM-COLABIOCLI Recommendation for Venous Blood Sampling” has been developed [30], which outlines a series of practical suggestions designed to improve and harmonize the blood drawing process. This document is a valuable resource for ensuring consistency and best practices in phlebotomy and can serve as a reference for local standard operating procedures (SOPs). In addition to regular venipuncture procedures, the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM), in collaboration with the European Society for Emergency Medicine and the European Society for Emergency Nursing, has developed a comprehensive set of guidelines specifically tailored for blood sampling in the emergency department [31]. These guidelines address all the critical aspects of blood collection in this high-pressure environment, applying the GRADE methodology to ensure a robust and evidence-based approach. The topics covered are extensive, including pre-hospital blood sampling, proper tube labeling, sampling posture, phlebotomist education, choice of disinfectant, use of gloves, tourniquet placement, and handling of devices like catheters and butterfly needles. Additionally, the guidelines explore the use of devices that facilitate vein detection, the implementation of pneumatic tube systems, rainbow sampling, point-of-care testing, and preanalytical quality indicators. These guidelines are designed to help standardize practices across emergency departments, ensuring that blood sampling is performed in such a way that maximizes accuracy and quality of results while minimizing potential errors and complications.

Impact of hemolysis on sample integrity and acceptance

Last but not least, hemolysis remains one of the most significant sources of concern for clinical laboratories worldwide [32]. This issue is not limited by geography or scale of the laboratory, as it affects both small clinics and large hospital networks. Hemolysis, which occurs when red blood cells (and likely other blood cells, i.e., leukocytes and platelets) are spuriously injured, may have deep implications for test results, potentially leading to inaccurate or unreliable data [32]. Given its widespread impact, understanding the causes of hemolysis and implementing preventive strategies are critical for ensuring the quality and integrity of laboratory tests. The fact that hemolysis remains a prevalent concern across such diverse settings underscores its significance and the ongoing need for improvement in preanalytical procedures [33].

Why is hemolysis so critical for clinical laboratories? There are several compelling reasons behind this concern. First and foremost, hemolysis is relatively common, accounting for over 3 % of all routine samples submitted for testing [32]. As already highlighted, hemolyzed specimens represent a significant proportion of unsuitable samples, with studies showing that they account for between 40 and 70 % of all specimens unfit for laboratory testing [32]. Hemolysis is not just one of many potential issues, as it is the leading cause of specimen rejection, occurring four to five times more frequently than the second most common issue. The impact of hemolysis extends beyond the inconvenience of rejecting samples – it directly affects the reliability of test results. Many laboratory tests, especially those that involve measuring intracellular components or those with absorbance interference, become unreliable or invalid when performed on hemolyzed specimens. In these cases, laboratory professionals are often forced to suppress these tests, which can delay diagnosis and compromise clinical decision-making [33]. The clinical implications are far-reaching, as erroneous results or delayed testing can adversely affect patient care. Therefore, addressing hemolysis and minimizing its occurrence should be a priority in clinical laboratories to ensure the accuracy and timeliness of diagnostic outcomes.

For decades, visual inspection has been the only means for identifying and classifying hemolyzed specimens in clinical laboratories. While this approach has been widely relied upon, it has several drawbacks [34]. The accuracy of visual inspection depends on various individual factors, including the genetic composition of the retina, eye anatomy, and underlying conditions that may affect color recognition. Furthermore, environmental factors, particularly the amount and type of light exposure, can significantly influence the individual ability to detect hemolysis. As a result, this method is inherently subjective and prone to error. To address these limitations, the diagnostic industry has developed the so-called serum indices, which offer a much more reliable and objective tool for detecting and classifying interferences like hemolysis, icterus, and lipemia [35]. Serum indices are derived from absorbance measurements at different wavelengths, which are often instrument-specific, providing a semi-quantitative representation of the levels of these interferences in the sample. This innovation allows laboratory staff to assess sample quality with greater precision and consistency. Moreover, serum indices offer the advantage of being cost-effective and having minimal impact on instrument performance, as they do not require additional reagents or complex processes. Serum indices are now incorporated into the vast majority of clinical chemistry analyzers, many coagulometers, and even some immunoassay platforms and blood gas analyzers (detecting hemolysis in whole blood) [36], further enhancing the ability to minimize biased test results and improve the overall quality of laboratory diagnostics [33].

In an effort to harmonize the management of hemolysis in clinical laboratories and standardize best practices, the EFLM has developed a set of practical recommendations [37]. These guidelines aim to ensure that hemolysis is consistently identified and appropriately managed across different laboratory settings. First and foremost, the EFLM advocates that the quality of the sample, including the presence of hemolysis, should always be checked before testing. This step is crucial to ensure that the sample is suitable for analysis, thus preventing the delivery of unreliable test results. Whenever possible, the presence and degree of hemolysis should be assessed automatically using the hemolysis index, an objective and reliable tool for this purpose. In cases where the hemolysis index is unavailable, visual assessment remains a viable alternative, and in such instances it is suggested to compare sample color with a standardized color chart. Moreover, results from the hemolysis index assessment should always be transferred and stored within the laboratory information system (LIS), ensuring that this critical information is readily accessible to both the laboratory and clinical staff. The EFLM also proposes that consideration be given to including hemolysis index data in the laboratory report, allowing clinicians to better acknowledge sample quality. Ideally, test results of the hemolysis index should be converted into the corresponding plasma or serum hemoglobin concentration, preferably measured in g/L, to provide a more precise understanding of the level of hemolysis. Moreover, laboratories should develop and implement SOPs to ensure the standardized management of test results from hemolyzed samples. Finally, it is essential to incorporate both internal and external quality control materials to continuously monitor the analytical performance of the hemolysis index, guaranteeing the reliability and accuracy of this important tool [38]. These recommendations, when applied, can significantly improve the quality of laboratory diagnostics and reduce the risk of erroneous results due to hemolysis.

Conclusions

Significant progress has been made over recent years in addressing many of the crucial challenges associated with the preanalytical phase. Documents and guidelines that have been developed by the EFLM and other national and international scientific organizations have contributed to supporting and improving daily practice, providing valuable resources for better managing preanalytical issues [39], 40]. However, there is still more to be done, ongoing challenges that require continued attention and improvement, as attested by a recent study, which found that preanalytical errors may account for over 98 % of all errors throughout the total testing cycle [41]. With this positive outlook in mind, the scientific community must remain committed to advancing efforts and continuing to address these preanalytical challenges in the years ahead.