This is a Platinum Open Access Journal distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Impact of a novel strategy for critical values communication for the management of patients treated with clozapine Ruth Cano-Corres1, Siddarta Acebillo2,3, Francesc Campos Barreda1, Diego J. Palao2,4, Eugenio Berlanga-Escalera1 1 Department of Biochemistry, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain 2 Department of Mental Health, Corporació Sanitaria Parc Taulí de Sabadell, Barcelona. Departament of Psychiatry and Forensic Medicine, Autonomous University of Barcelona, Barcelona, Spain 3 Department of Mental Health, Parc Taulí Hospital Universitari, I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain 4 Centro de Investigación en Red de Salud Mental, CIBERSAM, Madrid, Spain ARTICLE INFO ABSTRACT Corresponding author: Introduction Dr. Ruth Cano-Corres ParcTauli 1, CP: 08208 Clozapine is an antipsychotic drug used to treat resis- Sabadell, Barcelona tant schizophrenia and other disorders. Based on the Spain Phone: 93.745.84.39 actual Spanish legislation, patients treated with clo- E-mail: rcano@tauli.cat zapine must undergo periodical haematological ex- aminations and treatment should be reviewed when Key words: clozapine, e-mail, haemogram alterations, the haemogram shows either a leukocyte count of patients’ safety, values communication ≤ 3500/mm3 or neutrophil count < 2000/mm3. An au- tomatic notification system has been developed to optimize patient management and it’s utility was assessed following the implementation of the new system. Page 458 eJIFCC2021Vol32No4pp458-466 R. Cano-Corres, S. Acebillo, F. Campos Barreda, D. J. Palao, E. Berlanga-Escalera Novel strategy for critical values communication for patients treated with clozapine Material and methods Administration (FDA) approved its use for resis- When clozapine (CLO) laboratory test request tant schizophrenia in 1990. In Spain, CLO was was made, a reflex complete blood count test re-introduced for clinical practice in 1993 under was also done. An automatic e-mail was sent by severe regulatory control conditions. All pa- the laboratory information system to the physi- tients treated with CLO must undergo haemato- logical examinations (haemogram cell counts), cian when a CLO was ordered and low leukocyte weekly during the first 18 weeks of treatment or neutrophil counts were detected, or when a and monthly during the lifelong treatment. The patient with an ordered CLO test did not attend AEMPS (Spanish acronym of Spanish Agency of the laboratory for blood drawing. Drugs and Sanitary Devices) (11) defined these Results conditions, that remain valid at the time of sub- mitting this manuscript. For patients with haemogram alterations, the time to take clinical action was significantly de- The AEMPS defines that, if the haemogram creased from 23 to 7 days (p = 0.02). Moreover, shows a leukocyte count less than 3500/mm3 the adherence to Spanish Agency of Drugs and or neutrophil under 2000/mm3, CLO treatment Sanitary Devices recommendations significantly must be reviewed, modifying drug dose or ana- increased from 45% to 76% (p = 0.02). For not lytic haemogram control frequency (Table 1). attending patients, the days out of control de- In Spanish population, agranulocytosis is a rare creased from 29 to 12 days, although it was not event, but the incidence of neutropenia and statistically significant (p = 0.06). leukopenia is estimated to be 3% and 1.3%, re- spectively (12). Conclusions To avoid unnecessary visits, patients receiving This strategy has allowed the compliance of le- CLO and attending our hospital are first directed gal requirements, the improvement of patient to the laboratory for blood drawing for the hae- safety, and the optimisation of clinical and labo- mogram analysis and then immediately to the ratory procedures. Mental Health Department for a visit with the  clinician or a specialised psychiatric nurse. Upon following the above practice, at the mo- INTRODUCTION ment of the clinical visit the haemogram results (leukocyte/mm3 and neutrophil/mm3) are not Clozapine (CLO) is an antipsychotic drug used in yet available and can’t be reviewed by psychi- resistant schizophrenia, schizophrenia with ex- atric professionals, delaying therapeutic mea- trapyramidal symptoms not responding to oth- sures for patients presenting with a leukocyte er drugs, or psychotic symptoms in Parkinson’s count of less than 3500 /mm 3 or neutrophil disease (1-7). count of under 2000/mm3. CLO was discovered in 1958, but in 1975 its Given the implication to patient safety, devel- commercialisation and prescription were de- oping a good laboratory result communication tained since some clinical cases of agranulocy- strategy is essential for clinical practice. A critical tosis, patients presenting neutrophil count un- result involving therapeutic modifications must der 0.5/mm3, were detected (9-10). be immediately informed to the physicians to Basing on subsequent studies including hae- ensure the best patient management, avoiding matological examinations, the Food and Drug unnecessary treatments or examinations. Page 459 eJIFCC2021Vol32No4pp458-466 R. Cano-Corres, S. Acebillo, F. Campos Barreda, D. J. Palao, E. Berlanga-Escalera Novel strategy for critical values communication for patients treated with clozapine Some international organisations have pub- A new laboratory test named “Clozapine patient lished guidelines and recommendations to control” (CLZ) was created. For patients treated ensure the appropriate information commu- with CLO, when CLZ was ordered by psychiatric nication between the laboratory and clinical physicians or nurses, a reflex haemogram test departments, like the Joint Commission on was also done, this could be differentiated from Accreditation of Health Care Organization the other haemograms. (JCAHO) (13) for laboratory accreditation in the Two different algorithms for automatic advice USA, or the Clinical and Laboratory Standards rules were created. Institute (CLSI) (14) in Europe. Employing automated rules ensures the detec- 1. Automatic advice rule: tion of 100% of the values requiring immediate leukopenia/neutropenia detected communication, minimize human errors and in a patient treated with CLO significantly reduce the time to communicate The rule was configured to send an automatic with the physicians, which in turn can prioritize e-mail when the following conditions were met: patient visits and results in an overall circuit CLZ test ordered, and leukocyte count < 3500/ optimization. mm3 or neutrophil count < 2000/mm3. In Spain, some studies have demonstrated that communicated values via e-mail only comprise To assure a quick response e-mails are sent to 1% of all the communications (15), and was a the physician or nurse ordering the test and novelty for our hospital. to three psychiatric physicians, three labora- tory specialists, and one laboratory secretary. In May 2018, our clinical laboratory implement- To confirm that information was received by ed a new laboratory information system (LIS), the Mental Health Department, it was estab- which made it possible to create informatics lished that the first psychiatric physician or algorithms to send an automatic e-mail when nurse reading the e-mail had to respond to the certain predefined criteria were met. Laboratory and take charge of the case. If after This strategy was first applied to patients treat- 24 hours there was no answer, laboratory staff ed with CLO for automatic notification of al- should contact the Mental Health Department tered haematological values, and patients not by phone. attending the laboratory. The purpose of this study was to evaluate the impact of a new au- The project began in March 2019 and the e-mail tomatic notification system employing infor- text was: “A leukopenia/neutropenia has been matics algorithms and e-mails in the clinical detected in the patient Hxxxx”. To ensure data management of patients treated with CLO. protection only patient clinical history number was included and the e-mail addresses em- MATERIALS AND METHODS ployed were the corporative ones. The new LIS employed by the laboratory was Three months later, the text was modified to Smartlis (Lab Technologies S.A.) v46®, which al- include AEMPS recommendations on treat- lows implementation of algorithms and informa- ment and analysis frequency modifications, tion fluxes with the Mental Health Department when a leukopenia/neutropenia was detected to develop a novel strategy of communication. (Table 1). Page 460 eJIFCC2021Vol32No4pp458-466 R. Cano-Corres, S. Acebillo, F. Campos Barreda, D. J. Palao, E. Berlanga-Escalera Novel strategy for critical values communication for patients treated with clozapine Table 1 AEMPS recommendations Haematological count Required action Leukocyte (mm3) Neutrophil (mm3) Continue same clozapine ≥ 3.500 ≥ 2.000 treatment Continue same clozapine treatment but haematological Between ≥3.000 and ≤3.500 Between ≥1.500 and ≤2.000 analysis every 2 weeks, until stabilisation or increased cellular count Stop clozapine treatment, and haematological analysis every day < 3.000 < 1.500 until resolution. Monitor possible infections. No re-introduction of the drug 1.1 Evaluation of rule utility from the total of laboratory advices to notify To investigate the utility of this rule the follow- critical results (mail and telephone advices). ing parameters were registered for each patient 1.2. Evaluation of proper CLZ requisition treated with CLO when leukopenia/neutrope- nia was detected: We also evaluated if CLZ test was properly or- dered, reviewing all the haemograms ordered a. AEMPS recommendations followed by by the Mental Health Department from July to the physician/nurse: Yes/No October 2019 (n=1811). When leukopenia/neu- b. Number of days to take a clinical tropenia was detected, we checked if the cor- decision responding patient was treated with CLO. All these parameters were obtained by review- ing patient histories and e-mail accounts. 2. Automatic advice rule: patient treated with CLO not attending Data obtained from March to December 2018 the laboratory for blood analysis (n=11) were compared to those from March to December 2019 (n=17), after implementing the Since many patients treated with CLO were ab- automatic notification. sent at the scheduled follow-up visit (neither laboratory analysis nor psychiatric visit), they The difference between AEMPS recommenda- remained uncontrolled until the next visit. To tions fulfilment was compared employing a X 2 reduce the time between follow-up visits, the test, and the time to take a clinical decision with new advice rule sent an e-mail to the coordi- a U Mann-Whitney test. nating nurse of the Mental Health Department Also, during March to December 2019, we cal- when a patient did not attend the laboratory for culated the percentage of advices made via mail the analysis, and a CLZ test was ordered. Thus, Page 461 eJIFCC2021Vol32No4pp458-466 R. Cano-Corres, S. Acebillo, F. Campos Barreda, D. J. Palao, E. Berlanga-Escalera Novel strategy for critical values communication for patients treated with clozapine psychiatric professionals could contact the pa- sending (1.06%). From the 17 communications, tient and a new analysis could be rescheduled. only two corresponded to inpatients, and the The text of the e-mail was: “Patient Hxxxx who other 15 corresponded to outpatients. had scheduled an analysis for CLZ on xx-xx-xx, These 17 advices (e-mails) corresponded to eight did not come to the laboratory”. To evaluate the patients: one patient presented five mail advices time without follow-up for these patients, the during the study period, one patient three ad- employed parameter was the number of days vices, one patient two advices, and the last five without follow-up: data of the follow-up analy- patients presented one advice each during the sis - data on the patient who did not go for labo- study period. ratory analysis. Three patients were men and five women and In order to assess whether time without follow- the average age was 32.5 years. up was reduced since this automatic rule was implemented, patients not going to the labo- 1.1. Evaluation of rule utility ratory for blood-drawing between December Confirmity to the AEMPS recommendations in- 2018 (n=16) and December 2019 (n=35) were creased significantly from 45% (5/11) for patients evaluated, and the differences in the number of in 2018, to 76% (13/17) for patients in 2019 (p = days without follow-up were compared using a 0.02). U Mann Whitney test. The MedCalc® v 7.2.1.0. statistical program was used for the statistical Table 2 shows the implemented clinical actions comparisons. for those patients. The number of days elapsed until the clinical ac- RESULTS tion was implemented significantly decreased 1. Automatic advice rule: from 23 days in the year 2018 to 7 days in 2019, leukopenia/neutropenia detected after the application of the advice (p = 0.02). in a patient treated with CLO From March-December 2019, 1.22% (17/1389) From March to December 2019, 1591 CLZ tests from all advices made in our laboratory em- were ordered, and 17 met criteria for e-mail ployed an automatic e-mail. Table 2 Implemented actions in patients with advice during 2019 and 2018 Number of patients Action 2019 2018 New haematological analysis control until leukocyte/ 9 1 neutrophil count recovery Stop clozapine 1 0 New haematological analysis + stop other drugs 2 0 No modifications 5 10 Page 462 eJIFCC2021Vol32No4pp458-466 R. Cano-Corres, S. Acebillo, F. Campos Barreda, D. J. Palao, E. Berlanga-Escalera Novel strategy for critical values communication for patients treated with clozapine 1.2. Evaluation of proper CLZ requisition significantly delay patient management (18), From July to October 2019, 1811 haemograms and it continues to be one of the most common were ordered by Mental Health Department. contributing factors to the development of ad- verse events (19). Data available in the literature We detected 3 leukopenia/neutropenia in pa- shows an error rate of 3.5% for all telephone tients treated with CLO that were not advised by calls made from laboratories (20). For this rea- e-mail because a haemogram instead of a CLZ son, automated informatics systems facilitating test was erroneously ordered by the psychiatric the generation of alerts for information trans- physician/nurse. Two corresponded to a patient mission ensure patient safety. However, these with a previous notice and the haematological strategies are not yet widely employed. In a alteration was already known. However, the last 2008 survey of critical value reporting, the one corresponded to a patient without previous College of American Pathologist found that only haematological disorders, thus the e-mail advis- 8.6% of 623 institutions communicate critical ing the alteration and the potential danger was values using wireless technologies. (21) In Spain not sent. e-mail notifications only comprise 1% of all the communications (15). 2. Automatic rule: patient treated with CLO not attending the laboratory These data are comparable to the results of our for blood-drawing study, in which 1,22% of the communications is made via e-mail after the implementation of During December 2019, 215 CLZ tests were the first advice rule. requested. Thirty-five patients (16.3%) did not present for blood drawing. All e-mails were sent In our laboratory, the implementation of a nov- to alarm them, and 27 were rescheduled within el LIS enabled the development of an automatic 1 month (77%). In December 2018, 149 patients communication system employing informatics had an analysis scheduled, 16 did not attend algorithms and e-mail to send an alert when (10.7%), and nine of them presented for analysis some established criteria were met. within 1 month (56.25%). For patients presenting haematological altera- The days without follow-up decreased from 29 tions, the implementation of the first rule has days in December 2018 to 12 days in December advanced the application of the required clini- 2019 after implementing the warning rule, al- cal action. Also the compliance of the AEMPS though statistical significance was not reached recommendations has significantly increased, (p = 0.06). although it was not applied for 24% of the cases (n=4). In two of the four cases, patients DISCUSSION were controlled in another hospital and for the other two cases the clinical specialist evalu- A quality reporting system is defined as the de- ated the patient and decided to continue with livery of correct results to the appropriate clini- the treatment and analysis frequency. This au- cians in a time frame that ensures patient safety tomatic strategy also ensured the detection of without overburdening both the clinicians and 100% of haemogram alterations. Some clinical laboratory team (16). situations, such as bacterial infections, may Communication of critical values and clinically cause leukocyte count elevations. In these cas- significant results is a Joint Commission patient es, decreases in leukocyte count caused by CLO safety goal (17). Failure in communication can treatment may be masked. Therefore, these Page 463 eJIFCC2021Vol32No4pp458-466 R. Cano-Corres, S. Acebillo, F. Campos Barreda, D. J. Palao, E. Berlanga-Escalera Novel strategy for critical values communication for patients treated with clozapine situations must be taken into account in this management. The demonstrated benefits of this type of patients. collaboration should motivate the adoption of As we have reported, most of the advices (85%) similar strategies in many other clinical ambits were sent to outpatients, who are the most of our hospital. Many patients treated with oth- benefited from employing this communication er drugs could benefit from this type of warning strategy. rules, for example those treated with azathio- prine which also cause agranulocytosis. It is important to remark that demanding the correct CLZ test is essential for the correct oper- Some experiences have been published in rela- ation of the circuit, to avoid the loss of leukope- tion to automated communication, using e-mail nia/neutropenia cases detected. In our opinion, or SMS, vs. oral communication. For example, in for the future, automatic systems which could Spain, an SMS system was implemented to noti- link patient treatment information with analyti- fy microbiological results with many useful ben- cal tests ordering could be essential to avoid er- efits, such as the reduction in the time of notifi- rors attributed to manual test ordering. cation, and elimination of risk errors when there For patients that usually renege on their vis- is no repetition of the information received its, the second reminder rule reduced the by the recipient to the laboratory staff (22). time these patients spent without follow-up. Another Italian study was performed employ- Statistically significant differences were not ing two instant notification systems: the short achieved, maybe due to the high standard de- message service (SMS) and an alert message on viation observed in both groups and the low the desktop computer (23). Computerised com- number of not attending patients in December munication demonstrated a reduction in notifi- 2018. Future studies with higher number of pa- cation time and yielded additional benefits: it tients would be probably required to find sig- eliminated the risk of errors occurring by phone nificant differences. notification and erroneous patient identification and test and value reporting, which occurs if the Moreover, the two rules allowed to identify a group of patients defined as “well-controlled read-back step is not used. patients”: patients without haematological al- All studies support the importance of the read- terations and generally adhering to the visits/ back step, our study established that if no answer analysis. For these patients, the frequency of were received 24 h after sending the advice their visits to the Mental Health Department had e-mail, laboratory staff would contact the Mental been spread and the quality of the clinical visit Health Department to ensure communication. improved. For instance, during the clinical visits Many studies have demonstrated that auto- physicians may spend more time giving recom- matic alerting systems reduce the time until the mendations for a healthy life and emotional as- provision of appropriate treatment in patients pects, instead of spending time reviewing labo- with critical laboratory results, showing a re- ratory data. duction of time until the resolution of patient Globally, all patients have benefited from the abnormality by 29% (24,25). In our study the re- application of both rules. duction of time until a clinical decision was ap- For the Mental Health Department, this strat- plied was significantly reduced by 67% (22.36 to egy is supposed to ensure the fulfilment of ac- 7.29) days, showing significant reductions than tual legislation and the improvement of patient published data. Page 464 eJIFCC2021Vol32No4pp458-466 R. Cano-Corres, S. Acebillo, F. Campos Barreda, D. J. Palao, E. Berlanga-Escalera Novel strategy for critical values communication for patients treated with clozapine CONCLUSION Madrid: Ministerio de Sanidad y Consumo; 1993. Avail- able at: http://www.ub.edu/legmh/disposici/cir1093. This strategy has allowed the compliance of le- htm. gal requirements, the improvement of patient 12. Pons A, Undurraga J, Batalla A, Beranrdo M. Clozapina safety, and the optimisation of clinical and labo- y agranulocitosis en España: ¿tenemos una población más segura? 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