Maximizing Safety in Cancer Treatment

Brigitta U. Mueller

Amy L. Billett

INTRODUCTION

In 1980, the American Society of Anesthesiologists was the first professional group to form a patient safety committee after reviewing a television exposé of anesthesia incidents. In the 1990s, the literature on medical errors started to become voluminous, and in 2014, PubMed (the search engine of the National Library of Medicine) listed more than 110,000 publications under the search term “medical error.”

In 1999, the Institute of Medicine (IOM) published its report To Err Is Human: Building a Safer Health Care System, citing an estimated 44,000 to 98,000 deaths in adults per year caused by medical errors.¹ The estimated total cost of measurable medical errors in the United States was $17.1 billion in 2008, which was 0.72 % of the $2.391 trillion spent on health care that year in the United States.²

Chemotherapy safety (or the lack thereof) came to the public’s attention in 1995, when the case of Betsy Lehman, a Boston Globe reporter, who died of an accidental overdose of cyclophosphamide, was prominently featured in the news media.³

Betsy Lehman, a 39-year-old woman, was being treated for breast cancer at the Dana Farber Cancer Institute in Boston. She died after receiving a fourfold overdose of cyclophosphamide. This was only discovered several months later during a routine review of her medical records. It was determined that the ordering physician had written “cyclophosphamide 4 g/sq m over four days” with the intention that the patient receive a total of 1 gram per square meter over 4 sequential days. However, the order was interpreted as prescribing 4 grams per square meter for each of 4 sequential days. Betsy Lehman died 3 weeks later from the cardiac complications ensuing from this massive overdose.

Errors can occur at any time during an encounter with the health care system, and include errors in diagnosing, treating, or preventing illness. Errors are due to many different factors, including lack of teamwork, stress, workload, and clerical mistakes, such as faulty transcriptions.⁴^,⁵^,⁶^,⁷^,⁸ The medical field has only begun to acknowledge this problem, to promote open discussion, and to apply techniques that have been proven effective in other high-risk fields.⁹ However, harm to patients due to errors remains common, despite more than a decade of improvement efforts.¹⁰

BACKGROUND

Several studies have demonstrated that errors can occur in every medical setting; however, vulnerable populations and high-risk procedures add additional challenges. The Agency for Healthcare Research and Quality (AHRQ) estimated that there were six million “hospital-acquired conditions” in 2010, of which 97,000 led to possibly preventable deaths. At this time, no comprehensive and reliable data exist on the ambulatory care error toll, despite the increasing importance of ambulatory care in overall management. Most publications describe interventions in the emergency room or during anesthesia, but few have addressed the special challenges involved in the treatment of children with complex disorders.¹¹^,¹² Slonim et al. surveyed hospitalized, nonnewborn patients in the United States and found a reported medication error rate of 1.81 to 2.96 per 100 discharges.⁸ An even more disturbing report was published by Kaushal et al.,¹³ who found 55 medication errors per 100 inpatient admissions at a single, leading pediatric teaching hospital.

Medication errors are made by both junior as well as experienced physicians. In a prospective study over a year, the total and significant error rate, respectively, per 1,000 orders, was 3.30 and 1.76 for attending physicians. A similar rate was found for residents and fellow trainees at any level: the error rate was 2.34 and 1.36 for second-year residents, 1.98 and 0.95 for third-year residents, and 0.81 and 0.54 for fourth-year residents and fellows. Similar data exist for nurses and nurse trainees.¹⁴^,¹⁵

Antineoplastic drugs often have a low therapeutic index, and an overdose easily leads to devastating consequences (excessive myelosuppression, renal toxicity, or even death), while underdosing may impact treatment efficacy. Furthermore, certain agents are highly toxic if administered by the wrong route (e.g., vincristine given intrathecally). An analysis of 140 errors reported by nurses in an adult oncology practice revealed multiple sources of mistakes: 39% were due to the wrong dose (body surface area not recalculated, a week’s dose given in 1 day, wrong vial used to mix dose); 21% were due to wrong duration of administration or given at the wrong time; 18% were due to the wrong drug (confused with other drug); and 14% were due to administration of the drug to the wrong patient.¹⁶

Children who are treated for cancer are of different ages and different body weights and may have specific organ deficiencies. Caregivers, especially nurses and physicians, must adjust their medication orders not only to the underlying disease and organ function but also to the age, weight, and height of the child. Although “fixed dosing” provides some measure of safety in adults because it brings familiarity with certain doses, the dosage is different for each child, and the dosage schedule often changes during the course of the treatment, because the child may lose weight or develop new organ dysfunctions. In a review of oral chemotherapy for children with acute lymphoblastic leukemia, one or more errors were found with 17 of 172 (9.9%) medications prescribed.¹⁷ Rinke et al. queried a national, voluntary, Internet-accessible error reporting system (United States Pharmacopeia MEDMARX database) for all error reports from 1999 through 2004 that involved chemotherapy medications and patients younger than 18 years. Eighty-five percent (264) of the 310 reported pediatric chemotherapy errors reached the patient, and 49 (15.6%) required additional patient monitoring or therapeutic intervention. The most commonly involved chemotherapeutic agents were methotrexate (15.3%), cytarabine (12.1%), and etoposide (8.3%).¹⁸ Pediatric patients are also particularly susceptible to the risk of harm in errors involving home medication administration.¹⁹

Definitions

Understanding the field of patient safety requires an understanding of the terms used. The Joint Commission (TJC) investigates “sentinel events,” that is, events that signal the need for immediate investigation and response. Sentinel events are due to an unexpected occurrence involving death or serious physical or psychological injury (specifically loss of limb or function), or the risk thereof. When a reviewable sentinel event is reported to TJC, the health
care organization is required to share its root cause analysis. The events and their root causes are then recorded in a de-identified database. Between 1993 and June 2013, 26 states and the District of Columbia reported over 7,400 sentinel events, most of them (4,844) occurring in hospitals. The three most common categories were “unintended retention of a foreign body,” “wrong-patient, wrong-site, wrong-procedure,” and “delay in treatment.” The most common reasons identified in root cause analyses include human factors, leadership issues and communication failures (http://www.jointcommission.org/sentinel_event.aspx). Many of these sentinel events then lead to the issue of a sentinel alert by TJC. As of March 2014, 51 sentinel alerts have been issued. Sentinel Events are reported to TJC voluntarily by an accredited organization or reported via the complaint process.

Medication errors are defined as errors that occur at any stage in the medication use process, from ordering to dispensing to administration to monitoring (Table 18.1). The vast majority of medication errors are harmless, but 1% to 2% cause injury. However, an additional 5% are “near misses” that fail to cause injury by chance or because they are intercepted before reaching the patient. Medication errors are frequent and cause substantial resource waste because of the need to discard the wrong medication, the additional work in preparing a new dose, and the necessary reporting and cause analysis.

Diagnostic errors or a delay in diagnosis may be caused by a failure to employ indicated tests, the use of inappropriate or outmoded tests or therapy, or a failure to act on results of monitoring or testing. A study of 130 successful litigation claims against the National Health Service in England involving fatalities in children listed delayed or failed diagnosis in 47% of the cases.²⁰

Treatment errors include errors in the performance of an operation, procedure, or test; errors in administering the treatment; errors in the dose or method of using a drug (see below), as well as avoidable delays in treatment or response to an abnormal test. Furthermore, we now recognize that errors in prevention, such as failure to provide prophylactic treatment or the inadequate monitoring or follow-up of treatment, play an important role as well.²¹

TABLE 18.1 Definitions of Events Related to Drug Administration

Term	Definition	Example(s)
Harm occurred
Adverse event (AE)	Harm in a patient administered a drug but not necessarily caused by a drug	Traumatic death while receiving mercaptopurine
Adverse drug event (ADE)	Harm caused by a drug
Expected ADE (e.g., adverse drug reaction)	A usually predictable or dose-dependent effect of a drug that is not the principal effect for which the drug was chosen (e.g., listed in package insert)	Myelosuppression from chemotherapy Cisplatin-induced emesis in a patient receiving appropriate antiemetics
Unexpected ADE	Not identified in nature, severity, or frequency in the sponsor’s brochure or package insert	Common in relatively new drugs
Serious ADE (SAE)	Fatal/life threatening, permanently disabling, leading to or prolonging hospitalization, causing congenital anomaly, any drug overdose	Delayed methotrexate clearance with need for intervention
Sentinel event	Unexpected occurrences involving death or serious physical or psychological injury or risk thereof	Intrathecal administration of vincristine
Preventable ADE	An ADE that could have been prevented by any means	Cisplatin-induced emesis in patient not receiving antiemetics
Harm may have occurred
Medication error	An error that occurs in any stage of the medication process, including ordering, transcribing, dispensing, administering, monitoring	30-min delay in mesna administration
Harm did not occur
Potential ADE (near miss)	A medication error with the potential for harm	A 10-fold overdose of narcotic that is intercepted before administration

Health care-associated infections (HAIs) are a major cause of morbidity and mortality in children and adults. Central line-associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTIs), ventilator-associated pneumonias (VAPs), and surgical site infections (SSIs) have successfully been targeted with standardization of care. The incidence of CLABSIs in intensive care or pediatric oncology patients has been reduced by using standardized “bundles” for insertion and maintenance of the catheters, as well as through the use of ancillary measures, such as daily baths with chlorhexidine.²²^,²³^,²⁴^,²⁵ Preventable pressure ulcers may occur in critically ill children or patients with limited mobility and can be avoided by paying meticulous attention to vulnerable areas, such as bony prominences. Especially vulnerable are neonatal patients, where the administration of oxygen via nasal prongs or masks can cause skin defects, sometimes with lasting cosmetic consequences.²⁶^,²⁷

Legal and Financial Implications

Medical malpractice litigation, or personal-injury law (tort), has become not only a large legal and financial enterprise but also a political issue that has been discussed intensively over the last few decades.²⁸^,²⁹ Unfortunately, the culture of “finding and punishing the culprits,” as practiced by litigators, is in stark contrast to the nonpunitive approach that seeks to find the problems in the system and relies heavily on open reporting.²⁹ The willingness or ability to discuss and report errors may be influenced by state or national circumstances; for example, Maryland has strong peer-review protection laws, while Florida does not.³⁰

Adverse drug events (ADEs) are also costly. In a review of 190 ADEs, 60 of them deemed preventable, the additional length of stay associated with the event was 2.2 days, and the increase in cost was $2,595 overall and $4,685 for preventable events. This does
not include the costs for malpractice suits or the loss of income suffered by the patients. In an analysis of medication-related malpractice claims, Rothschild et al. found that the mean costs of defending a malpractice claim for preventable and other outpatient ADEs were similar (mean, $64,700 to $74,200) but considerably higher for preventable inpatient ADEs ($376,500).³¹

RECOGNIZING AND REPORTING OF PROBLEMS

Different techniques have been used to assess error rates in the medical setting.³²^,³³ The five main techniques are:

1. The voluntary reporting method is strongly influenced by the culture of the organization and is most helpful in an environment where reporting is not perceived as being followed by a punitive action. In general, this method does not produce quantitative information, because only a small number of events are being reported, but it can furnish very valuable qualitative information about both errors and “near misses.”³⁴ Another form of voluntary reporting is the Morbidity and Mortality Conference. Although often helpful in better understanding complex cases and the outcome and consequences of different pathologies, these conferences are fraught with hindsight bias, focus on diagnostic errors, and are infrequently and rather randomly used in most academic institutions.³⁵ Autopsies have been shown to detect potentially fatal misdiagnoses in 20% to 40% of cases but are being used even less often as the frequency of autopsies decreases.³⁶
2. The chart review method is readily available and commonly used, but is often inaccurate because of the lack of precise documentation and hindsight bias. It is also very labor intensive and dependent on consensus and confidence of the reviewers.³⁷ This may change as electronic medical record systems that allow for standardized ordering and reporting become more widely implemented.³⁸
3. The observation method measures actual errors during drug administration and dispensing. This method is more accurate and complete than chart reviews but does require trained observers (nurses, pharmacists, or pharmacy technicians). Staff members are observed and their activities documented by the observer. The notes are then compared with the written prescription order. In this method, deviations in timing of medication delivery, omission of doses, and the actual dosage administered are determined and can later be reviewed and graded by a medication safety committee in regard to significance.³³^,³⁹ Direct observation is extremely labor intensive and rarely practical outside of funded research efforts.
4. The practitioner intervention method involves keeping a formal log of interactions that occur daily between pharmacists and nurses or physicians to clarify an order. This method predominantly captures events at the prescribing stage and is also very useful for detecting “near misses.”³³ Pharmacists are asked to keep track of any orders that were incorrectly written, that needed clarification, or that violated a safety precaution (e.g., penicillin ordered in a patient with penicillin allergy). Nurses keep track of events where the pharmacy delivered the wrong drug or at the wrong time or to the wrong patient. This technique is valuable to measure the amount of “rework” that occurs.
5. Computerized monitoring has become more widely available as information technology has matured.⁴⁰^,⁴¹ A data source that has been used for several years is the detecting of adverse events by reviewing the administrative codes used for diagnoses and procedures (ICD-9-CM and CPT codes). However, coding is done weeks to months after discharge, and is generated for reimbursement and legal goals, and is thus not very reliable for detecting adverse events.⁴² Laboratory data can be searched more easily, because the data are mostly in numeric form.⁴³ Examples are the doubling of creatinine levels and high serum drug levels. With the advent of electronic medical records, it has become easier to perform either concurrent or retrospective trend analyses.

Event Reporting

Internal reporting of adverse events is required by health care institutions, both to meet external regulatory requirements and to provide information to leadership to prevent other such events in the future. Each institution defines what should be reported and how it is carried out based on institutional priorities, relevant state law, and guidelines or requirements from regulatory agencies, accreditation agencies such as TJC, and payors such as the Centers for Medicare and Medicaid Services. Although event reports themselves are not placed in the patient chart, disclosure to the patient/family should be documented in a progress note that also describes the event. In most, but not all, states, event reports are considered peer review material and protected from legal discovery. As an organization focuses on patient safety and a nonpunitive reporting environment, the number of event reports tends to increase, a sign of success rather than failure. However, event reporting vastly underestimates the occurrence of problems.⁴⁴^,⁴⁵

Root Cause Analysis

Root cause analysis (RCA) is a retrospective technique to analyze an event after it occurs. The technique has been widely used in industrial accidents.⁴⁶ In 1997, TJC mandated the use of the RCA technique whenever a sentinel event occurs. The RCA technique can be used to identify what occurred, why it occurred, and to propose changes that would prevent it from happening again. The health care-specific model for an RCA focuses on four major areas: leadership, human factors, information, and the environment. TJC offers a framework to assist organizations in performing an RCA (www.jointcommission.org).

Occurrence Screens

Most, if not all, health care organizations utilize dedicated staff members or automated reports to screen for the occurrence of specific events in the hospital, such as transfer to the intensive care unit, death, readmission within 72 hours, and return to the operating room within 48 hours. These events are reviewed to determine the degree of preventability. Events with a high degree of preventability or events with a fatal outcome can then be further investigated with a RCA.

Adverse Drug Event Reporting

Not all adverse events are due to errors or mistakes. Adverse event collection and reporting is a routine part of every clinical trial. In oncology, the Common Toxicity Criteria (CTC), maintained by the National Cancer Institute, are commonly used to grade the severity of an adverse event. The procedure for the reporting of an ADE or serious adverse event depends on the phase of the clinical trial, the approval status of the drug (investigational vs. noninvestigational), and the seriousness of the event. However, reporting of ADEs does not end with the approval of a drug by the Food and Drug Administration (FDA). Potentially fatal adverse events related to cancer drugs might become apparent only decades after FDA approval of a drug.⁴⁷ The Center for Drug Evaluation and Research (CDER) oversees the MedWatch program, through which physicians and other health care professionals can report medication errors directly to the FDA. This one-page form, available at http://www.fda.gov/medwatch/, is “intended for use by health professionals and consumers for voluntary reporting of adverse events and product problems related to medications (drugs
or biologics, except vaccines), medical devices (including in vitro diagnostics), special nutritional products (dietary supplements, infant formulas, medical foods), and other FDA-regulated medical products” (wording from FDA Web site).

Failure Mode and Effects Analysis

In contrast to a retrospective RCA, a failure mode and effects analysis (FMEA) is a prospective technique that can be applied to any process without the occurrence of a sentinel event or near miss.⁴⁸ This multidisciplinary approach was first developed and applied in the aerospace industry. The analytic approach defines the steps involved in the process of interest and then analyzes each step for potential failures. Three factors are considered:

▪ Failure modes: what could go wrong?
▪ Failure causes: why could the failure happen?
▪ Failure effects: what would be the consequences of each failure?

Consideration of the likelihood of a failure, the severity of the consequences of a failure, and probability of the failure being detected allows each potential failure to be assigned a risk-priority number (RPN = severity × probability × detection). The team can then model or implement changes to those steps with the highest RPN. Repetitive FMEAs can be carried out over time to assess the impact of changes made. This technique has been successfully applied to the chemotherapy administration process in children with cancer and can lead to the more rapid adaptation of safety interventions, such as the use of preprinted order sets.⁴¹ It has also been used during the implementation of computerized order entry systems for pediatric chemotherapy.⁴⁹

Disclosure of Errors

As mentioned earlier, there might be regulatory reporting requirements, especially if an investigational drug or experimental protocol design is involved. Although disclosure to the patient and the family is encouraged and appropriate, this is often the most difficult part for the care providers involved.⁵⁰ A recent survey studied the opinions of members of a health plan and found that full disclosure of any errors or mistakes reduced the likelihood of changing physicians and increased patient satisfaction, trust, and positive emotional response.⁵¹ However, the number of people who would seek legal advice was not lowered by full disclosure. The overwhelming majority of responders (98.8%) wanted to be told of an error, and 87% would ask for financial compensation if any harm occurred. Another study confirmed this finding: 76% of surveyed people wanted to be informed immediately of any medical error and to receive full disclosure of the extent of the problem.⁵² More than 90% of respondents were in favor of reporting errors to government agencies (92%), state medical boards (97%), and hospital committees (99%). The hospital’s and/or physician’s risk management group thus needs to be notified of any potentially harmful errors to guide any necessary responses in case of media notification or legal action. Although some have shown that disclosure correlates with a decreased malpractice rate, much concern remains. In addition to disclosing errors to patients, staff involved in events with significant harm to patients should be offered appropriate support services.⁵³

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