Tissue Plasminogen Activator Overdose in Acute Ischemic Stroke Patients Linked to Poorer Functional Outcomes

Tissue Plasminogen Activator Overdose in Acute Ischemic Stroke Patients Linked to Poorer Functional Outcomes Demetrios J. Sahlas, MSc, MD,*† Linda Gould, RPN,† Richard H. Swartz, MD, PhD,‡ Naufal Mohammed, MD,†x Rhonda McNicoll-Whiteman, RN,† Fahd Naufal, BSc,jj and Wieslaw Oczkowski, MD*†

Background: The dose of intravenous tissue plasminogen activator (tPA) administered in acute ischemic stroke patients is calculated using the patient’s weight (0.9 mg/kg). Patients are rarely weighed before treatment in actual practice, although overestimating patient weights leads to higher doses of tPA, which may adversely influence outcome. Methods: We investigated the weight used to calculate the dose of tPA compared to the actual measured weight in consecutive acute ischemic stroke patients treated over a 4-year period at our center. The rate of intracranial hemorrhage (ICH), discharge modified Rankin Scale (mRS) score, and mortality at 3 months were compared between groups, according to accuracy of the dose of tPA. Results: We found that 140 of 164 (85%) acute ischemic stroke patients treated with tPA had a measured weight documented in the chart after treatment. Of these, 13 patients received $1.0 mg/kg and 16 patients received #0.8 mg/kg, based on a comparison of the weight used for the tPA dose calculation and the subsequent measured weight. Four of 13 (31%) patients treated with $1.0 mg/kg of tPA developed ICH. Patients who inadvertently received higher doses of tPA had a lower likelihood of a good functional outcome at discharge (mRS score 0-2; 0% v 34%; P 5 .009). No difference in 3-month mortality was observed, although patients who were not weighed in hospital had a threefold increase in discharge mortality (21% v 7%; P 5 .019). Conclusions: Our findings provide support for the practice of accurately weighing all acute ischemic stroke patients before thrombolysis. Key Words: Acute stroke—medical errors—thrombolytic therapy—tissue plasminogen activator. Ó 2014 by National Stroke Association

From the *Divisions of Neurology; xGeneral Internal Medicine, Department of Medicine; jjSchool of Graduate Studies, Global Health Program, Faculty of Health Sciences, McMaster University, Hamilton; †Central South Ontario Regional Stroke Centre, Hamilton General Hospital–Hamilton Health Sciences, Hamilton, Ontario; and ‡Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. Received November 29, 2012; revision received January 2, 2013; accepted January 2, 2013. Supported by the M.G. DeGroote Professorship in Stroke Management (D.J.S.), McMaster University, Hamilton, Ontario, Canada. Address correspondence to Demetrios J. Sahlas, MSc, MD, Hamilton General Hospital, Room 706, McMaster Wing, 237 Barton St E, Hamilton, Ontario, Canada, L8L 2X2. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.01.004

Thrombolysis using intravenously administered tissue plasminogen activator (IV tPA) represents the standard of care for treatment of acute ischemic stroke. The National Institute of Neurological Disorders and Stroke (NINDS) tPA stroke study established the efficacy of IV tPA at a dose of 0.9 mg/kg within 3 hours of symptom onset,1 although patients were not actually weighed before administration of the drug.2 The European Cooperative Acute Stroke Study III (ECASS III) further established efficacy between 3 and 4.5 hours of symptom onset.3 The use of IV tPA in acute ischemic stroke is associated with an increased risk of symptomatic intracranial hemorrhage (ICH; 4-6%), and an even greater likelihood of asymptomatic ICH (10%).1,4,5 Initial dose-finding trials suggested increased risks of ICH with doses .0.95 mg/kg6,7 and

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greater rates of ICH using higher doses of IV tPA have been reported in the cardiac literature.8,9 Even small amounts of ICH may have unforeseen clinical sequelae.10,11 The benefits of IV tPA at a higher dose in the original ECASS trial (1.1 mg/kg) were offset by greater rates of hemorrhagic complications, although an additional contributing factor may have been the prolonged treatment window of 6 hours in this trial.12 The dose of IV tPA administered for the treatment of acute ischemic stroke is calculated using the patient’s weight, up to a maximum of 90 mg for those who weigh $100 kg, although a reported or estimated weight is often used in actual practice, given time restrictions and other perceived limitations involved in weighing the patient. Patients weighing .100 kg receive the maximum dose of tPA and are therefore routinely administered ,0.9 mg/kg. These patients often have worse outcomes and are more likely to deteriorate after treatment.13,14 Underestimating a patient’s weight might likewise result in an insufficient or ineffective dose of tPA.13 Conversely, overestimating a patient’s weight results in overcalculating the dose of tPA, which has previously been linked to an increased risk of any ICH and for symptomatic ICH after adjusting for possible confounders, such as age, baseline National Institutes of Health Stroke Scale (NIHSS), and major early computed tomographic (CT) findings.15 We set out to determine: (1) the proportion of acute ischemic stroke patients who actually had their weight measured in the acute phase of their presentation to our center; (2) whether estimated or reported weights were accurate, and whether errors were more frequently errors in underestimation (resulting in a dose of #0.8 mg/kg) or overestimation (resulting in a dose of $1.0 mg/kg); (3) whether an increase in ICH on brain imaging was noted in the proportion of patients who received a dose of tPA $1.0 mg/kg; and (4) whether outcomes were worse (discharge modified Rankin Scale [mRS] and mortality) in the proportion of patients who received a dose of tPA $1.0 mg/kg.

Methods Approval for an observational study, based on retrospective chart review, was obtained from the Research Ethics Board at Hamilton Health Sciences. Data over a 4-year period (May 1, 2005 to April 30, 2009) were retrieved on all patients treated with tPA for acute ischemic stroke at the Hamilton General Hospital, Regional Stroke Centre for Central South Ontario, Canada. The population characteristics (age and sex) and initial stroke severity according to the NIHSS scores was tabulated, as were clinical factors known to be related to the risk of ICH, such as blood pressure, blood glucose, platelet count, and international normalized ratio (INR). Outcome measures included mRS score at discharge and

discharge mortality. Brain imaging was independently reviewed in all cases to confirm the presence or absence of ICH. Patients admitted to our stroke unit are routinely weighed if they are medically stable. The weight used to calculate the dose of tPA was compared to the measured weight in all patients subsequently weighed, and patients were then divided into groups according to whether an accurate dose of tPA was administered (0.9 6 10%, or 0.81-0.99 mg/kg), patients were underdosed (#0.8 mg/kg), or patients were overdosed ($1.0 mg/ kg). Patients who were underdosed were further subdivided into those who were inadvertently underdosed and those weighing .100 kg who received the maximum dose of tPA (90 mg) and were therefore underdosed according to protocol. Statistical analyses were performed using commercially available SPSS software (version 14; SPSS, Inc, Chicago, IL). For example, the Mann–Whitney U test (2-tailed) was used for comparing mean NIHSS scores and the Pearson Chi-square test (2-tailed) for comparing discharge mortality rates between weighed and unweighed patients.

Results The 164 patients ranged from 23 to 96 years of age (mean 70.0 6 14.6 years). Seventy-five of 164 (45.7%) study participants were women. One hundred forty of 164 (85%) patients had a measured weight documented in the chart after treatment. Patients who were not weighed during hospitalization had greater mean NIHSS scores on admission (15 v 11; P 5 .014) and a threefold increase in discharge mortality (21% v 7%; P 5.019; Table 1). Eight of 140 patients received the maximum dose of 90 mg of tPA, based on a weight .100 kg. Twenty-one of 132 (15.9%) of the remaining patients (in whom documentation of a dose miscalculation was possible) received a dose of tPA in excess of 610% of the proper dose. Eight additional patients (6.1%) received #0.8 mg/kg of tPA, while 13 (9.8%) patients received $1.0 mg/kg of tPA (Table 2). Patients receiving $1.0 mg/kg tPA had a lower likelihood of a good functional outcome at discharge (mRS score 0-2; 0% v 34%; P 5 .009), in addition to a trend for increased mortality (15% v 6%; not significant; Table 2). Twenty-five (17.9%) of the 140 patients developed any hemorrhagic transformation of their ischemic stroke (Table 3). Four of 13 (31%) of the patients treated with $1.0 mg/kg of tPA developed some hemorrhagic transformation of their ischemic stroke, compared to 21 of 129 (16.3%) of the patients who received ,1.0 mg/kg of tPA (P 5 .16; not significant).

Discussion Up to half of all patients admitted to hospital are never weighed.16 In emergency department (ED) and intensive

POORER OUTCOMES IN ACUTE STROKE WITH tPA OVERDOSE

Table 1. Demographic information of patients treated with tissue plasminogen activator for acute ischemic stroke who were weighed after admission compared to those who were not weighed during their hospital stay Weighed patients, n 5 140

Unweighed patients, n 5 24

Age, y (mean 6 SD) 69.6 6 14.9 72.8 6 13.3 Women, % 47 38 Mean NIHSS score 11 15* SBP, mm Hg (mean 6 SD) 157 6 27 160 6 35 DBP, mm Hg (mean 6 SD) 84 6 17 84 6 21 Glucose, mmol/L 7.2 6 2.6 7.6 6 2.3 (mean 6 SD) Platelets, 3109/L 254 6 66 243 6 68 (mean 6 SD) INR 1.0 6 .1 1.0 6 .1 Discharge mRS score 3 4 Discharge mortality, % 7 21* Abbreviations: DBP, diastolic blood pressure; INR, international normalized ratio; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; SBP, systolic blood pressure. *Statistically significant difference between groups.

care unit (ICU) settings, where weight-dependent medication doses are frequently used, problems with estimation of a patient’s weight have been well documented. Errors of .20% are made between 10% and 20% of the time by attending physicians, residents, nurses, and paramedics, and errors of .10% occur in up to half of all cases.17-21 In acute stroke management, several single-center studies have been published that confirm that stroke physicians are no better at estimating weight than their ED and ICU counterparts, and that errors may negatively impact outcomes. Despite a rate of errors of .10% of only

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12.1% in the retrospective Multicenter rt-PA Acute Stroke Survey, increased rates of ICH were observed in the highest dosage quintile.15 About half of all patients had a dosing error of ,1%, even though patients were not apparently weighed. The authors raised concern that ‘‘actual’’ weights may have been retrospectively determined by evaluation of the dose of IV tPA administered.15 In the prospective, observational Weight Approximation in Stroke before Thrombolysis (WAIST) study, the rate of estimation errors by the treating physicians was 38.2%, with one-third of patients receiving a dose of tPA .10% from the optimal dose.13 By comparison, the rate of equivalent dosing errors in the NINDS study was only 14.8%,2 suggesting that dosing errors may play a greater role in actual practice than in organized pharmaceutical trials. In a small, single-center study, only 29 of 45 (64%) acute ischemic stroke patients treated with IV tPA at Yale-New Haven Hospital had a recorded weight during admission. Of these patients, 86% were incorrectly dosed (38% underdosed; 48% overdosed). Three of 9 (33%) patients receiving high doses developed intracerebral hemorrhage.22 Another single-center study found that 38% of patients receiving tPA used an inaccurate weight, with roughly half of these being overestimates and half underestimates.23 In our center, incorrect estimates were more often overestimates. Four of 13 (31%) overdosed patients developed ICH, 1 of whom died. This 31% risk of bleeding is much higher than the global risk of 6% to 10% among all patients and comparable to previous studies, suggesting that overestimation of weight results in overdosing patients and therefore increases the risk of bleeding. Overdosage of tPA in acute ischemic stroke patients has been previously linked to increased risks of ICH,15 although a similar finding was not observed in the WAIST study.13 Of greater concern was our observation that patients

Table 2. Demographic information of patients treated with tissue plasminogen activator for acute ischemic stroke, according to accuracy of tissue plasminogen activator dose administered

Age, y (mean 6 SD) Women, % Mean NIHSS score SBP, mm Hg (mean 6 SD) DBP, mm Hg (mean 6 SD) Glucose, mmol/L (mean 6 SD) Platelets, 3109/L (mean 6 SD) INR Discharge mRS score Discharge mortality, %

Overdose (.1.0 mg/kg), n 5 13

Accurate dose (0.8-1.0 mg/kg), n 5 111

Underdose (,0.8 mg/kg), n58

Max dose (,0.8 mg/kg), n58

72.2 6 16.7 61 12 156 6 33 78 6 17 6.9 6 3.0 272 6 75 1.0 6 .1 4 15

69.1 6 16.0 46 11 155 6 24 83 6 12 8.2 6 2.0 251 6 66 1.0 6 .1 3 7

62.6 6 17.8 63 12 166 6 37 85 6 12 7.3 6 2.0 263 6 69 1.1 6 .1 3 0

78.1 6 9.0 25 10 164 6 44 99 6 17 9.3 6 6.5 251 6 45 1.0 6 .1 3 0

Abbreviations: DBP, diastolic blood pressure; INR, international normalized ratio; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; SBP, systolic blood pressure.

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Table 3. Demographic information of patients treated with tissue plasminogen activator for acute ischemic stroke with intracranial hemorrhage subsequently identified on brain imaging compared to those without intracranial hemorrhage on brain imaging

ICH, n 5 25

No ICH, n 5 115

Age, y (mean 6 SD) 68.8 6 15.6 69.2 6 18.0 Women, % 28 51 Mean NIHSS score 12 11 SBP, mm Hg (mean 6 SD) 150 6 27 158 6 26 DBP, mm Hg (mean 6 SD) 80 6 15 84 6 17 Glucose, mmol/L 7.3 6 2.4 7.2 6 2.6 (mean 6 SD) 240 6 68 256 6 53 Platelets, 3109/L (mean 6 SD) INR 1.0 6 .1 1.0 6 .1 Discharge mRS score 3 3 Discharge mortality, % 8 7 Abbreviations: DBP, diastolic blood pressure; ICH, intracranial hemorrhage; INR, international normalized ratio; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; SBP, systolic blood pressure.

receiving an overdose of tPA were less likely to experience a good functional outcome (mRS score 0-2; P 5 .009) regardless of whether they developed ICH. That patients who were not weighed at our center had a threefold increase in discharge mortality (21% v 7%; P 5 .019) is concerning, because this represents a subgroup with poor outcomes in whom it is not possible to determine whether dosing errors played a role. A similar observation was made in the Multicenter rt-PA Acute Stroke Survey (19% v 12%; P 5 .017) and has likewise been noted in the cardiac literature.24 Confirming whether IV tPA overdose is indeed associated with increased ICH and poorer outcomes remains challenging if patients with the poorest outcomes cannot be included in the analysis. Not obtaining accurate patient weights makes it impossible for an institution to ascertain whether a link exists with adverse outcomes. Patients with acute ischemic stroke are frequently unable to communicate effectively or provide their own weights.13 However, there has traditionally been no readily available, time-effective method to measure the weight of stroke patients in most emergency room settings. Numerous alternatives to visual estimation of weights have been published, involving various combinations of measurements of height, waist, hip, or arm circumferences, caliper skin measurements, and body surface area calculations. There has been considerable published literature reporting the utility of these estimates for ensuring accurate dosing and resuscitation efforts.13,18,21 While better than visual estimates, these techniques still err frequently, causing both under- and overdos-

13,18

Moreover, measurements of height, waist, and ing. hip circumference in the setting of hyperacute stroke treatment do not seem practical.12 Acute stroke treatment decision cannot be delayed by the time it would take to accurately perform these measures. It seems bizarre to consider doing so when a readily available solution is apparent—namely, weighing the patient. Current practice guidelines for acute stroke care are silent on the issue of obtaining accurate patient weights.25 A recent analysis of data from the NINDS tPA stroke study led to the suggestion that estimated weights are sufficient for treatment of acute ischemic stroke using tPA.2 However, estimation errors were much less common in the NINDS tPA stroke study than in other studies,13 which are possibly even more common in actual practice. Given the potentially critical importance of accurate dosing in the acute stroke setting, proper body weight determination should likely be considered standard of care before initiating tPA. Based on the results of this quality assurance study, we were successful in advocating with colleagues and hospital administration for resources to support a change in practice in our ED. It was agreed that obtaining a stroke patient’s actual weight both quickly and efficiently was desirable, and a dedicated stretcher with a built-in scale (Prime Series Electric Stretcher; Stryker Medical, Kalamazoo, MI) was purchased (list price $13,500 CAD [approximately $13,688 USD]) for the exclusive use of stroke patients as part of the acute stroke protocol at our center After successful implementation of this protocol, a decision was made to expand the fleet of ED stretchers with weighing capability to include all resuscitation and trauma bays. In conclusion, the estimation of a patient’s weight in the acute setting can lead to overcalculation of the tPA dose, which is associated with poorer functional outcomes at our center. Existing technology can eliminate this issue, and stroke thrombolysis teams can successfully advocate for this change in practice. At our institution, every potential candidate for thrombolytic treatment of acute ischemic stroke now has their weight measured before the administration of tPA. In the future, we plan to compare patient outcomes after implementation of our new protocol, in order to ascertain whether weighing acute ischemic stroke patients before thrombolytic treatment has a beneficial impact on clinical outcomes.

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