Background The visit to the emergency department (ED) constitutes a brief, yet an important point in the continuum of medical care. The aim of our study was to evaluate the continuity of care of adult ED visitors.
Background
The visit to the emergency department (ED) constitutes a brief, yet an important point in the continuum of medical care. The aim of our study was to evaluate the continuity of care of adult ED visitors.Methods We retrospectively reviewed all ED discharge summaries for over a month 's period. The ED chart, referral letter and the patient's primary care file were reviewed. Data collected included: age, gender, date and hour of ED visit, documentation of ED referral and ED discharge letter in the primary care file.
Methods
We retrospectively reviewed all ED discharge summaries for over a month 's period. The ED chart, referral letter and the patient's primary care file were reviewed. Data collected included: age, gender, date and hour of ED visit, documentation of ED referral and ED discharge letter in the primary care file.Results 359 visits were eligible for the study. 192 (53.5%) of the patients were women, average age 54.1 ± 18.7 years (mean ± SD). 214 (59.6%) of the visits were during working hours of primary care clinics ("working hours"), while the rest were "out of hours" visits. Only 196 (54.6%) of patients had a referral letter, usually from their family physician. A third (71/214) of "working hours" visits were self referrals, the rate rose to 63.5% (92/145) of "out of hours" visits (p < 0.0001). The ED discharge letter was found in 50% (179/359) of the primary care files. A follow-up visit was documented in only 31% (111/359). Neither follow up visit nor discharge letter were found in 43% of the files (153/359).
Results
359 visits were eligible for the study. 192 (53.5%) of the patients were women, average age 54.1 ± 18.7 years (mean ± SD). 214 (59.6%) of the visits were during working hours of primary care clinics ("working hours"), while the rest were "out of hours" visits. Only 196 (54.6%) of patients had a referral letter, usually from their family physician. A third (71/214) of "working hours" visits were self referrals, the rate rose to 63.5% (92/145) of "out of hours" visits (p < 0.0001). The ED discharge letter was found in 50% (179/359) of the primary care files. A follow-up visit was documented in only 31% (111/359). Neither follow up visit nor discharge letter were found in 43% of the files (153/359).Conclusions We have found a high rate of ED self referrals throughout the day together with low documentation rates of ED visits in the primary care charts. Our findings point to a poor continuity of care of ED attendees.
Conclusions
We have found a high rate of ED self referrals throughout the day together with low documentation rates of ED visits in the primary care charts. Our findings point to a poor continuity of care of ED attendees.

Background The emergency department (ED) is intended to treat medical urgencies or emergencies, but a large proportion of visits are due to problems that could be treated in the primary care setting [ 1 , 2 ]. ED services are available 24 hours a day while primary care facilities have limited service hours. In the Israeli health system patients can be referred to the ED by their family practitioner, or by other community health providers, or be self referred. Recently many out of hours community based services have been established but without a significant reduction in visiting rates to in-hospital ED. The visit to the ED constitutes a brief, yet an important point in the continuum of medical care. In today's era of cost effectiveness and increasingly competent primary care physicians, ambulatory investigation, treatment and follow-up have largely replaced prolonged and costly hospitalizations [ 3 , 4 ]. The ED visit however, remains a cross-road which may mark a sudden change in the patient's medical condition. In many cases it may result in introducing new medications, withdrawing others and recommendation of further investigations. The family practitioner is the one expected to coordinate and carry out the treatment and follow-up. The new information given from the ED should be effectively delivered to the family practitioner, the modality usually used is the discharge letter. The continuation of treatment between hospital departments and the primary care physician had been issued in several studies using discharge letters audit [ 5 - 7 ]. Raval et. al. assessed the adequacy of the discharge summary in reporting important investigative results and future management plans in patients hospitalized and discharged with a diagnosis of heart failure [ 5 ]. They found substantial inadequacies in communicating to the community physician that may have implications for continuity of care and subsequent clinical outcome. Wilson et. al. examined the reliability, effectiveness, accuracy and timeliness of hospital to general practitioner information transfer by discharge summaries. In a retrospective audit of 569 patient discharge summaries and related medical records they found that summaries written for patients discharged from hospital were estimated to be received by the patient-nominated general practitioner in 27.1% of cases [ 6 ]. Bolton et al assessed the quality of communications between hospitals and general practitioners. The general practitioner's(GP) name was recorded in 88% of audited records. Few inaccuracies were detected in the medications recorded in the discharge summaries, and on contrary to Wilson et al 77% of discharge summaries were received by the GP [ 7 ]. The continuity of care between the ED and the primary care physician had been assessed for children with asthma [ 8 ] but we did not find data about the continuity of care for adults. To evaluate the continuity of care after ED visits, we evaluated the ED referral and discharge letters, their content, and the documentation of the ED visit in the patients' primary care files. We have focused on discharges from the internal medicine ED. We expected that in these cases the patients would be followed up by their family practitioner.
Background
The emergency department (ED) is intended to treat medical urgencies or emergencies, but a large proportion of visits are due to problems that could be treated in the primary care setting [ 1 , 2 ]. ED services are available 24 hours a day while primary care facilities have limited service hours. In the Israeli health system patients can be referred to the ED by their family practitioner, or by other community health providers, or be self referred. Recently many out of hours community based services have been established but without a significant reduction in visiting rates to in-hospital ED.The visit to the ED constitutes a brief, yet an important point in the continuum of medical care. In today's era of cost effectiveness and increasingly competent primary care physicians, ambulatory investigation, treatment and follow-up have largely replaced prolonged and costly hospitalizations [ 3 , 4 ]. The ED visit however, remains a cross-road which may mark a sudden change in the patient's medical condition. In many cases it may result in introducing new medications, withdrawing others and recommendation of further investigations. The family practitioner is the one expected to coordinate and carry out the treatment and follow-up. The new information given from the ED should be effectively delivered to the family practitioner, the modality usually used is the discharge letter.The continuation of treatment between hospital departments and the primary care physician had been issued in several studies using discharge letters audit [ 5 - 7 ]. Raval et. al. assessed the adequacy of the discharge summary in reporting important investigative results and future management plans in patients hospitalized and discharged with a diagnosis of heart failure [ 5 ]. They found substantial inadequacies in communicating to the community physician that may have implications for continuity of care and subsequent clinical outcome. Wilson et. al. examined the reliability, effectiveness, accuracy and timeliness of hospital to general practitioner information transfer by discharge summaries. In a retrospective audit of 569 patient discharge summaries and related medical records they found that summaries written for patients discharged from hospital were estimated to be received by the patient-nominated general practitioner in 27.1% of cases [ 6 ]. Bolton et al assessed the quality of communications between hospitals and general practitioners. The general practitioner's(GP) name was recorded in 88% of audited records. Few inaccuracies were detected in the medications recorded in the discharge summaries, and on contrary to Wilson et al 77% of discharge summaries were received by the GP [ 7 ]. The continuity of care between the ED and the primary care physician had been assessed for children with asthma [ 8 ] but we did not find data about the continuity of care for adults.To evaluate the continuity of care after ED visits, we evaluated the ED referral and discharge letters, their content, and the documentation of the ED visit in the patients' primary care files. We have focused on discharges from the internal medicine ED. We expected that in these cases the patients would be followed up by their family practitioner.Methods The study was conducted in the district medical center (Kaplan), serving more than 500,000 inhabitants, and in 12 primary care clinics (32 family practitioners), of The Clalit Health Services in the Rehovot region, Israel. In Israel the entire population have a national health insurance by law and each citizen can choose to be a member of one of four HMOs. Every member of the Clalit Health Services, the largest HMO in Israel, is registered to a single family physician, and have a medical record in his physician's clinic. Visits to the emergency department are regulated in the national health insurance law. A referral by a physician or by ambulance is free of charge, but this referral should be with a referral letter and not by a phone call to the ED or to the patient. A self referral may cost the patient a co-payment of up to 100 USD. We reviewed retrospectively all the charts of the ED visits for a period of one month, excluding the visits to the pediatric and the gynecologic-obstetrics EDs (see flow-chart 1). 5,898 visits documented that month, resulted in 4,256 discharges and 1,642 hospitalizations. There were 1,564 discharges from the general ED. Trauma, surgery and orthopedics accounted 2,209 discharges and the rest 483 were from other specialties (ophthalmology, ENT, dermatology etc.). Inclusion criteria were: visit to the general ED, age above 18 years, discharge to the community (not hospitalized) at that visit, living and getting medical care in a family medicine group practice in the Rehovot region. Visits due to accidents, trauma, surgery, orthopedics, ENT, ophthalmology and other specialities were excluded from the study. The 1,564 discharges from the general ED were reviewed and 359 were found to be eligible to this study. Two physicians reviewed independently each ED medical chart. Data extracted included: age and gender of the patient, attendance date and hour, self referral, or a referral by a physician and the final diagnosis in the discharge letter. In cases of referrals the content and format of the referral letter were assessed, including: hand writing quality and whether the referring physician referred the patient with a specific question (for example: rule out new onset angina pectoris, suspected pneumonia, please make a chest X ray etc.). Continuity of communication and care: The primary care files of ED visitors were retrieved and checked for the existence of the ED discharge letter and comments about the visit in the follow-up chart. If the discharge letter and / or any comment on the ED visit in the follow-up chart had been found the case was defined as "a case with good continuity of care". The cases in which the family physician was the referring physician we looked for documentation of the encounter prior to ED attendance. Visits to the ED were divided into  "working hours" visits  – when the visit took place during working hours of primary care clinics in the community (Sunday to Thursday from 08:00 to 20:00, and Friday 08:00 to 14:00), and  "out of hours" visits  when primary care clinics in the community are closed (from 20:00 to 08:00 weekdays, and weekends from 14:00 on Friday to 08:00 on the following Sunday). A referral letter  was defined as "any document written by a medical authority in the community prior to the index ED visit", including referrals from family practitioners, other practitioners in the community and arrival by an ambulance. A recurrent visit to the ED  was defined as a patient's visit to ED within less than two weeks from a previous visit with the same complaint, when in both cases the patient was not hospitalized. Diagnoses at discharge  were coded for a specific diagnosis and for the system involved according to the ICPC coding system. Statistical analysis:  Data was analyzed using distribution analysis and χ 2  tests to investigate the association between categorized variables. Student's t tests were used to analyze continuous variables. The analysis was performed using the SPSS package.
Methods
The study was conducted in the district medical center (Kaplan), serving more than 500,000 inhabitants, and in 12 primary care clinics (32 family practitioners), of The Clalit Health Services in the Rehovot region, Israel.In Israel the entire population have a national health insurance by law and each citizen can choose to be a member of one of four HMOs. Every member of the Clalit Health Services, the largest HMO in Israel, is registered to a single family physician, and have a medical record in his physician's clinic. Visits to the emergency department are regulated in the national health insurance law. A referral by a physician or by ambulance is free of charge, but this referral should be with a referral letter and not by a phone call to the ED or to the patient. A self referral may cost the patient a co-payment of up to 100 USD.We reviewed retrospectively all the charts of the ED visits for a period of one month, excluding the visits to the pediatric and the gynecologic-obstetrics EDs (see flow-chart 1). 5,898 visits documented that month, resulted in 4,256 discharges and 1,642 hospitalizations. There were 1,564 discharges from the general ED. Trauma, surgery and orthopedics accounted 2,209 discharges and the rest 483 were from other specialties (ophthalmology, ENT, dermatology etc.).Inclusion criteria were: visit to the general ED, age above 18 years, discharge to the community (not hospitalized) at that visit, living and getting medical care in a family medicine group practice in the Rehovot region. Visits due to accidents, trauma, surgery, orthopedics, ENT, ophthalmology and other specialities were excluded from the study. The 1,564 discharges from the general ED were reviewed and 359 were found to be eligible to this study.Two physicians reviewed independently each ED medical chart. Data extracted included: age and gender of the patient, attendance date and hour, self referral, or a referral by a physician and the final diagnosis in the discharge letter. In cases of referrals the content and format of the referral letter were assessed, including: hand writing quality and whether the referring physician referred the patient with a specific question (for example: rule out new onset angina pectoris, suspected pneumonia, please make a chest X ray etc.).Continuity of communication and care: The primary care files of ED visitors were retrieved and checked for the existence of the ED discharge letter and comments about the visit in the follow-up chart. If the discharge letter and / or any comment on the ED visit in the follow-up chart had been found the case was defined as "a case with good continuity of care".The cases in which the family physician was the referring physician we looked for documentation of the encounter prior to ED attendance.Visits to the ED were divided into  "working hours" visits  – when the visit took place during working hours of primary care clinics in the community (Sunday to Thursday from 08:00 to 20:00, and Friday 08:00 to 14:00), and  "out of hours" visits  when primary care clinics in the community are closed (from 20:00 to 08:00 weekdays, and weekends from 14:00 on Friday to 08:00 on the following Sunday).A referral letter  was defined as "any document written by a medical authority in the community prior to the index ED visit", including referrals from family practitioners, other practitioners in the community and arrival by an ambulance.A recurrent visit to the ED  was defined as a patient's visit to ED within less than two weeks from a previous visit with the same complaint, when in both cases the patient was not hospitalized.Diagnoses at discharge  were coded for a specific diagnosis and for the system involved according to the ICPC coding system.Statistical analysis:  Data was analyzed using distribution analysis and χ 2  tests to investigate the association between categorized variables. Student's t tests were used to analyze continuous variables. The analysis was performed using the SPSS package.Results During the study period there were 359 ED visits that were eligible to be included in the study (table  1 , flow chart 1). . 214 (59.6%) visited the ED during the "working hours" of primary care clinics, 28 (7.8% of all visits) were recurrent visits to the ED. Table 1 Data on 359 visitis to the Emergency Department All visits (359) Referral letter (196) Self referral (163) P Value* Gender   Women - 192 (53.5%) 106 (54%) 86 (52.7%) NS   Men – 167 (46.5%) 96 (46%) 77 (47.3%) Age  (years, mean ± SD) 54.1 ± 18.7 55.1 ± 19.0 52.9 ± 18.4 NS Age distribution  <45 127 (35.4%) 68 (34.7%) 59 (36.2%) NS  46–65 105 (29.3%) 53 (27%) 52 (31.9%)  66–75 63 (17.5%) 38 (19.4%) 25 (15.3%)  >75 64 (17.8%) 37 (18.9%) 27 (16.6%) Visit time  Working hours – 214 (59.6%) 143 (73%) 71 (43.6%) <0.0001  Out of hours – 145 (40.4%) 53 (27%) 92 (56.4%) * – p Value for comparison between patients with referral letter and self referrals Out of all ED visits only 196 (54.6%) patients had a referral letter, the rest were self-referrals. Referral letters were mainly from the family practitioner (147/196, 75%), 14 (7%) from other practitioners in the community, and 35 (18%) of referrals were by ambulance. The referral letters from the community were legible in 43.4% (70/161), 46.5% (75/161) were barely legible and 10% (16/161) illegible. In only 25/161 letters (15.7% of the referrals) a specific question was asked by the referring physician and in another 32 (20.2%) there was only a general question. The main diagnostic groups according to the ICPC were: respiratory (15.7%), digestive system (18.1%), musculo-skeletal (15.2%) and cardio-vascular (11%). In 9.6% of the cases the discharge letter did not contain a specific diagnosis and the diagnosis fell in the "general" category. The most common specific diagnoses were: chest pain (5.9%), abdominal pain (3.9%), other respiratory tract infections (3.7%), asthma (3.1%), back pain (2.8%), COPD exacerbation (2.8%) headache (2.5%), nephrolithiasis (2.5%), vertigo or dizziness (2.5%) and gastroenteritis (2.3%). The "out of hours" visitors tended to be younger (52.2 ± 17.5 vs. 55.4 ± 19.5, p = NS) (table  1 ). A third of the "working hours" visits (71/214) were self referrals as opposed to 63.5% (92/145) of "out of hours" visits (p < 0.0001). Table  2  compares the referring practitioners according to ED visiting hours. Table 2 Comparison between the source of referral, in 196 visits according to ED visit hours* The referring practitioner "Working hours"** "Out of hours" Total The Family practitioner 125 (87.5%) 22 (41.5%) 147 By ambulance 16 (11%) 19 (36%) 35 Other practitioner*** 2 (1.5%) 12 (22.5%) 14 Total 143 (100%) 53 (100%) 196 * – p < 0.0001 ** – "working hours" visits – when the visit was during the working hours of primary care clinics in the community *** – private practitioners, and out of hours commmunity emergency clinics In 147 cases the reffering physician was the family physician, documentation of the ED referral was found in 32% (47/147) of primary care files. The ED discharge letter was found in 50% (179/359) of the primary care files. A follow-up visit was documented in only 31% (111/359). Neither follow up visits nor discharge letters were found in 43% of the files (153/359). No associations between clinic characteristics (size, place) or family practitioner qualification and ED visit documentation was found.
Results
During the study period there were 359 ED visits that were eligible to be included in the study (table  1 , flow chart 1). . 214 (59.6%) visited the ED during the "working hours" of primary care clinics, 28 (7.8% of all visits) were recurrent visits to the ED.Data on 359 visitis to the Emergency Department* – p Value for comparison between patients with referral letter and self referralsOut of all ED visits only 196 (54.6%) patients had a referral letter, the rest were self-referrals. Referral letters were mainly from the family practitioner (147/196, 75%), 14 (7%) from other practitioners in the community, and 35 (18%) of referrals were by ambulance. The referral letters from the community were legible in 43.4% (70/161), 46.5% (75/161) were barely legible and 10% (16/161) illegible. In only 25/161 letters (15.7% of the referrals) a specific question was asked by the referring physician and in another 32 (20.2%) there was only a general question.The main diagnostic groups according to the ICPC were: respiratory (15.7%), digestive system (18.1%), musculo-skeletal (15.2%) and cardio-vascular (11%). In 9.6% of the cases the discharge letter did not contain a specific diagnosis and the diagnosis fell in the "general" category. The most common specific diagnoses were: chest pain (5.9%), abdominal pain (3.9%), other respiratory tract infections (3.7%), asthma (3.1%), back pain (2.8%), COPD exacerbation (2.8%) headache (2.5%), nephrolithiasis (2.5%), vertigo or dizziness (2.5%) and gastroenteritis (2.3%).The "out of hours" visitors tended to be younger (52.2 ± 17.5 vs. 55.4 ± 19.5, p = NS) (table  1 ). A third of the "working hours" visits (71/214) were self referrals as opposed to 63.5% (92/145) of "out of hours" visits (p < 0.0001). Table  2  compares the referring practitioners according to ED visiting hours.Comparison between the source of referral, in 196 visits according to ED visit hours** – p < 0.0001 ** – "working hours" visits – when the visit was during the working hours of primary care clinics in the community *** – private practitioners, and out of hours commmunity emergency clinicsIn 147 cases the reffering physician was the family physician, documentation of the ED referral was found in 32% (47/147) of primary care files. The ED discharge letter was found in 50% (179/359) of the primary care files. A follow-up visit was documented in only 31% (111/359). Neither follow up visits nor discharge letters were found in 43% of the files (153/359). No associations between clinic characteristics (size, place) or family practitioner qualification and ED visit documentation was found.Discussion The Emergency Department (ED) acts as a link between community and hospital based medicine. In Israel a patient who needs non elective admission to a hospital unit must pass through the ED, either with a referral note from a medical practitioner, or as a self referral. Most ED visits, however, do not result in hospitalization, and many could be regarded as primary health care problems [ 1 , 2 , 9 ]. These patients are discharged directly from the ED to the community and further care of the family practitioner. A visit to the ED is generally not prompted by a benign complaint; The most common reasons for referral include, chest pain, asthma exacerbations and nephrolithiasis, subsequent follow up by the family practitioner can be vital. It was found that most children do not have outpatient follow-up after an ED asthma visit [ 8 ]. However, those patients that present for outpatient follow-up have an increased likelihood for repeat ED asthma visits, and this visit should be a key opportunity to prevent future ED asthma visits. The increasing role played by the ED in treating primary care problems has been discussed in a number of recent articles [ 9 - 11 ]. One aspect, which is important to the ED team, is the logistics and manpower needed to optimize the treatment of these non-urgent patients in ways that will not interfere with emergencies yet providing them adequate care. It is unclear whether the capability and quality of primary care services in the ED should be improved and compete with the community family physicians. This is true especially in Israel where there is a universal national health insurance and every patient can have a personal family practitioner. The continuity of comprehensive management is expected from the family practitioner, and is gaining importance nowadays [ 12 ]. To achieve this goal the communication between health care providers who treat the patient is mandatory. In the case of the ED visit, where we found many self referrals and referrals from other physicians, it becomes even more important. The modes of communication are the referral letter and the discharge letter. We have found that the referral letter can be improved both in style (printed instead of illegible hand writing) and content (the referring physician should define and clarify the reasons for referral and his expectations). These problems exist in discharge letters as well [ 13 ]. Documentation in the primary care file was poor, only one third of referrals were documented and less than 60% of discharges. This figure is between the 27%–77% that was found by others [ 6 , 7 ]. A possible bias is that some follow-up visits were to specialists. But in the case of discharge from the general medicine ED we presume that most patients were advised to return to their family physicians. It is well known that medical notes are poor in other areas, Miller et al [ 14 ] found documentation of only 15% of prescriptions given by family practitioners. They explained one of the causes for this discrepancy as the need of double writing (both the prescription itself and in the medical notes). By introducing carbon copy prescriptions, they achieved an 82% documentation rates in patients' files. Opila [ 15 ] found documentation in out patient medical records greatly improved after employing quality control and a feedback system. With the introduction of computerized medical files in primary care clinics in our region, the need of "double writing" will disappear, and this in turn should dramatically improve documentation rate of referrals and discharges to the ED; particularly if a computerized reminder system is used to encourage follow up of referrals by the family practitioner. Limitations Israeli health care system works in regard to ED use quite different from the US and other countries. Likewhise these results may not automatically be generalized to other health care systems. This study described the written communication between the emergency department and the primary care physician, which is the first and mandatory step in establishing continuation of care. This is only one of the four dimensions of continuity of care in family practice: chronological, geographical, interdisciplinary, and interpersonal [ 16 ]. Each of these dimensions may influence the quality of care and be evaluated and studied. Further study is needed to prove the link between documantion of ED visit and good contuniuity of care. Large scale prospective intervention studies are needed to prove that continuity of care between ED and the primary care physician improves outcome and saves money.
Discussion
The Emergency Department (ED) acts as a link between community and hospital based medicine. In Israel a patient who needs non elective admission to a hospital unit must pass through the ED, either with a referral note from a medical practitioner, or as a self referral. Most ED visits, however, do not result in hospitalization, and many could be regarded as primary health care problems [ 1 , 2 , 9 ]. These patients are discharged directly from the ED to the community and further care of the family practitioner. A visit to the ED is generally not prompted by a benign complaint; The most common reasons for referral include, chest pain, asthma exacerbations and nephrolithiasis, subsequent follow up by the family practitioner can be vital. It was found that most children do not have outpatient follow-up after an ED asthma visit [ 8 ]. However, those patients that present for outpatient follow-up have an increased likelihood for repeat ED asthma visits, and this visit should be a key opportunity to prevent future ED asthma visits.The increasing role played by the ED in treating primary care problems has been discussed in a number of recent articles [ 9 - 11 ].One aspect, which is important to the ED team, is the logistics and manpower needed to optimize the treatment of these non-urgent patients in ways that will not interfere with emergencies yet providing them adequate care. It is unclear whether the capability and quality of primary care services in the ED should be improved and compete with the community family physicians. This is true especially in Israel where there is a universal national health insurance and every patient can have a personal family practitioner.The continuity of comprehensive management is expected from the family practitioner, and is gaining importance nowadays [ 12 ]. To achieve this goal the communication between health care providers who treat the patient is mandatory. In the case of the ED visit, where we found many self referrals and referrals from other physicians, it becomes even more important.The modes of communication are the referral letter and the discharge letter. We have found that the referral letter can be improved both in style (printed instead of illegible hand writing) and content (the referring physician should define and clarify the reasons for referral and his expectations). These problems exist in discharge letters as well [ 13 ].Documentation in the primary care file was poor, only one third of referrals were documented and less than 60% of discharges. This figure is between the 27%–77% that was found by others [ 6 , 7 ]. A possible bias is that some follow-up visits were to specialists. But in the case of discharge from the general medicine ED we presume that most patients were advised to return to their family physicians.It is well known that medical notes are poor in other areas, Miller et al [ 14 ] found documentation of only 15% of prescriptions given by family practitioners. They explained one of the causes for this discrepancy as the need of double writing (both the prescription itself and in the medical notes). By introducing carbon copy prescriptions, they achieved an 82% documentation rates in patients' files. Opila [ 15 ] found documentation in out patient medical records greatly improved after employing quality control and a feedback system.With the introduction of computerized medical files in primary care clinics in our region, the need of "double writing" will disappear, and this in turn should dramatically improve documentation rate of referrals and discharges to the ED; particularly if a computerized reminder system is used to encourage follow up of referrals by the family practitioner.Limitations Israeli health care system works in regard to ED use quite different from the US and other countries. Likewhise these results may not automatically be generalized to other health care systems. This study described the written communication between the emergency department and the primary care physician, which is the first and mandatory step in establishing continuation of care. This is only one of the four dimensions of continuity of care in family practice: chronological, geographical, interdisciplinary, and interpersonal [ 16 ]. Each of these dimensions may influence the quality of care and be evaluated and studied. Further study is needed to prove the link between documantion of ED visit and good contuniuity of care. Large scale prospective intervention studies are needed to prove that continuity of care between ED and the primary care physician improves outcome and saves money.
Limitations
Israeli health care system works in regard to ED use quite different from the US and other countries. Likewhise these results may not automatically be generalized to other health care systems. This study described the written communication between the emergency department and the primary care physician, which is the first and mandatory step in establishing continuation of care. This is only one of the four dimensions of continuity of care in family practice: chronological, geographical, interdisciplinary, and interpersonal [ 16 ]. Each of these dimensions may influence the quality of care and be evaluated and studied. Further study is needed to prove the link between documantion of ED visit and good contuniuity of care. Large scale prospective intervention studies are needed to prove that continuity of care between ED and the primary care physician improves outcome and saves money.Conclusion ED visits may have important implications for the patient and his family practitioner. The high rate of ED self referrals together with low documentation rates of ED visits in the primary care charts result in poor continuity of care of ED visitors.
Conclusion
ED visits may have important implications for the patient and his family practitioner. The high rate of ED self referrals together with low documentation rates of ED visits in the primary care charts result in poor continuity of care of ED visitors.Competing interests None declared.
Competing interests
None declared.Authors' contributions All authors read and approved the final manuscript. VS Conceived and designed the study, participated in the collection, analysis and interpretation of data and drafted the manuscript. KE Participated in the statistical analysis, interpretation of data and draft of the manuscript.OY participated in the design of the study, data collection and interpretetio hand draft of the manuscript. SN participated in the design of the study, interpretation of data and draft of the manuscript. All authors have read and approved the final manuscript. Figure 1 Emergency department (ED) visits that included in the study
Authors' contributions
All authors read and approved the final manuscript.VS Conceived and designed the study, participated in the collection, analysis and interpretation of data and drafted the manuscript. KE Participated in the statistical analysis, interpretation of data and draft of the manuscript.OY participated in the design of the study, data collection and interpretetio hand draft of the manuscript. SN participated in the design of the study, interpretation of data and draft of the manuscript. All authors have read and approved the final manuscript.Pre-publication history The pre-publication history for this paper can be accessed here:
Pre-publication history
The pre-publication history for this paper can be accessed here:


Background The brain-derived protein S100B has been shown to be a useful marker of brain injury of different etiologies. Cognitive dysfunction after cardiac surgery using cardiopulmonary bypass has been reported to occur in up to 70% of patients. In this study we tried to evaluate S100B as a marker for cognitive dysfunction after coronary bypass surgery with cardiopulmonary bypass in a model where the inflow of S100B from shed mediastinal blood was corrected for.
Background
The brain-derived protein S100B has been shown to be a useful marker of brain injury of different etiologies. Cognitive dysfunction after cardiac surgery using cardiopulmonary bypass has been reported to occur in up to 70% of patients. In this study we tried to evaluate S100B as a marker for cognitive dysfunction after coronary bypass surgery with cardiopulmonary bypass in a model where the inflow of S100B from shed mediastinal blood was corrected for.Methods 56 patients scheduled for coronary artery bypass grafting underwent prospective neuropsychological testing. The test scores were standardized and an impairment index was constructed. S100B was sampled at the end of surgery, hourly for the first 6 hours, and then 8, 10, 15, 24 and 48 hours after surgery. None of the patients received autotransfusion.
Methods
56 patients scheduled for coronary artery bypass grafting underwent prospective neuropsychological testing. The test scores were standardized and an impairment index was constructed. S100B was sampled at the end of surgery, hourly for the first 6 hours, and then 8, 10, 15, 24 and 48 hours after surgery. None of the patients received autotransfusion.Results In simple linear analysis, no significant relation was found between S100B levels and neuropsychological outcome. In a backwards stepwise regression analysis the three variables, S100B levels at the end of cardiopulmonary bypass, S100B levels 1 hour later and the age of the patients were found to explain part of the neuropsychological deterioration (r = 0.49, p < 0.005).
Results
In simple linear analysis, no significant relation was found between S100B levels and neuropsychological outcome. In a backwards stepwise regression analysis the three variables, S100B levels at the end of cardiopulmonary bypass, S100B levels 1 hour later and the age of the patients were found to explain part of the neuropsychological deterioration (r = 0.49, p < 0.005).Conclusions In this study we found that S100B levels 1 hour after surgery seem to be the most informative. Our attempt to control the increased levels of S100B caused by contamination from the surgical field did not yield different results. We conclude that the clinical value of S100B as a predictive measurement of postoperative cognitive dysfunction after cardiac surgery is limited.
Conclusions
In this study we found that S100B levels 1 hour after surgery seem to be the most informative. Our attempt to control the increased levels of S100B caused by contamination from the surgical field did not yield different results. We conclude that the clinical value of S100B as a predictive measurement of postoperative cognitive dysfunction after cardiac surgery is limited.

Background Despite the fact that incidence figures between 4–79% have been reported for cognitive dysfunction after cardiac surgery [ 1 ], diagnostic steps are seldom taken to diagnose this impairment. The golden standard for detecting cognitive dysfunction is neuropsychological tests, which are complex and difficult to use as a routine procedure. Lately the brain derived protein S100B has been proposed as a simple method for detecting brain dysfunction after cardiac surgery [ 2 - 5 ]. The protein is a member of the larger S100 family, where S100B is one isoform, and considered to be brain specific, and the other is the S100A isoform [ 6 ]. The S100B chain is uniform in contrast to the S100A chain which exhibits several subgroups. The dimers of interest in studies concerning cerebral events are those containing S100B (S100BB and S100A1B). The physiological roles of S100B are pleiotropic including neurotrophic and neuroprotective functions, mediated by calcium dependent regulation of phosporylation, enzyme activation and proliferation [ 6 ]. On the other hand, high concentrations of S100B have been shown to be toxic and induce apoptosis in neuronal cell cultures [ 7 , 8 ]. At least five experimental studies have indicated a possible role of S100B in learning and memory function, three of which reported impaired memory and learning effects in transgenic S100B mice and two reported memory deficits after injection of S100B antiserum [ 9 - 13 ]. Several studies in humans suffering from stroke of different ethiologies, have shown a rather strong correlation between serum levels of S100B and size of lesion(s) as well as outcome [ 14 - 17 ]. Lately a number of studies have addressed the question whether S100B can be considered as a marker for cognitive dysfunction after cardiac surgery; however the conclusions presented are disparate. One major reason for this could be the fact that S100B is present in high concentrations in shed mediastinal blood that is retransfused to the patient by cardiotomy suction and autotransfusion, thus obscuring the measured levels of S100B early after surgery. To date, only one study have been published where this contamination was taken into account [ 18 ]. We recently reported the half life of S100B in serum to be 25 min [ 19 ]. With the present study we wanted to use our knowledge of inflow and elimination to obtain a more reliable measurement of cerebral release of S100B after cardiac surgery and correlate it with neuropsychological outcome.
Background
Despite the fact that incidence figures between 4–79% have been reported for cognitive dysfunction after cardiac surgery [ 1 ], diagnostic steps are seldom taken to diagnose this impairment. The golden standard for detecting cognitive dysfunction is neuropsychological tests, which are complex and difficult to use as a routine procedure. Lately the brain derived protein S100B has been proposed as a simple method for detecting brain dysfunction after cardiac surgery [ 2 - 5 ]. The protein is a member of the larger S100 family, where S100B is one isoform, and considered to be brain specific, and the other is the S100A isoform [ 6 ]. The S100B chain is uniform in contrast to the S100A chain which exhibits several subgroups. The dimers of interest in studies concerning cerebral events are those containing S100B (S100BB and S100A1B). The physiological roles of S100B are pleiotropic including neurotrophic and neuroprotective functions, mediated by calcium dependent regulation of phosporylation, enzyme activation and proliferation [ 6 ]. On the other hand, high concentrations of S100B have been shown to be toxic and induce apoptosis in neuronal cell cultures [ 7 , 8 ]. At least five experimental studies have indicated a possible role of S100B in learning and memory function, three of which reported impaired memory and learning effects in transgenic S100B mice and two reported memory deficits after injection of S100B antiserum [ 9 - 13 ].Several studies in humans suffering from stroke of different ethiologies, have shown a rather strong correlation between serum levels of S100B and size of lesion(s) as well as outcome [ 14 - 17 ].Lately a number of studies have addressed the question whether S100B can be considered as a marker for cognitive dysfunction after cardiac surgery; however the conclusions presented are disparate. One major reason for this could be the fact that S100B is present in high concentrations in shed mediastinal blood that is retransfused to the patient by cardiotomy suction and autotransfusion, thus obscuring the measured levels of S100B early after surgery. To date, only one study have been published where this contamination was taken into account [ 18 ]. We recently reported the half life of S100B in serum to be 25 min [ 19 ]. With the present study we wanted to use our knowledge of inflow and elimination to obtain a more reliable measurement of cerebral release of S100B after cardiac surgery and correlate it with neuropsychological outcome.Methods Study design The study group comprised 56 patients who underwent coronary artery bypass graft (CABG) surgery at the Division of Cardiac Surgery, University Hospital MAS, Malmoe, Sweden and Department of Cardiothoracic Surgery, Lund University Hospital, Lund, Sweden. Only patients planned for elective CABG with cardiopulmonary bypass (CPB) as their sole procedure were included. The study protocol was approved by the local ethics committee, and patients gave a written informed consent before the study protocol was initiated. Patients with a history of stroke, transient ischemic attack (TIA), reversible neurological disorder (RIND), known carotid artery disease or other brain diseases were excluded. In order to avoid possible influence of renal disorder on the elimination of S100B, patients with known renal failure (Creatinin > 160 μmol/L) were excluded. The patients were examined for signs of neurological dysfunctions daily during the hospital stay by either experienced cardiac anesthesiologists or by experienced cardiac surgeons. Perioperative management Anesthesia was induced with midazolam 3–5 mg iv (Dormicum ® , Roche, Basel, Switzerland) or propofol (Diprivan ® , Zeneca Ltd, Cheshire, England) 10 mg/kg. It was subsequently maintained with fentanyl 10 μg/kg (Leptanal ® , Janssen Pharmaceutica, Beerse, Belgien), a continuous infusion of propofol 3–6 mg/kg/h or inhalation of isoflurane 0,5–1% (Forene ® , Abbott Laboratories). Nitrous oxide (Aga Industries, Stockholm, Sweden) was used before CPB but not during or after CPB. CABG surgery was performed during aortic cross clamping with the distal anastomosis preceding the proximal anastomosis. A tangential occluder replaced the cross-clamp during the proximal anastomosis. Antegrade cold S:t Thomas crystalloid cardioplegia was used (Cardioplegi ® , Pharmacia-Upjohn, Uppsala, Sweden) and administered in the ascending aorta and the anastomosed vein-grafts intermittently. Perfusion was performed with a roller pump (Cobe Industries, Denver, Colorado, USA). The perfusion catheters and circuit were made of polyvinylchloride in the line and silicon in the pumphead. The arterial cannulation was made in the ascending aorta and venous cannulation in the right atrium by a two-stage venous cannula. All circuits contained a heparin-coated 40 μm arterial filter (Cobe Sence, Cobe Industries) and a membrane oxygenator (Cobe Duo oxygenator, Cobe Industries). The circuit was primed with approximately 1000 ml of Ringer's lactate (Pharmacia-Upjohn), 250 ml 15% Mannitol (Pharmacia-Upjohn) and 75 mmol Addex tromethamine (Pharmacia-Upjohn). Perfusion flow was non-pulsatile with a flow rate of 2.4 l/min/m 2  at normothermia. The perfusate was cooled to approximately 32°C. Heparin (400 U/kg bodyweight) was given prior to cannulation and reversed with equal doses of protamine sulphate at decannulation. After surgery, the patients patient were transferred to the ICU for recovery and enrolled in the sampling scheme for S100B analysis. None of the patients received autotransfusion. S100-protein analysis and calculations Serum for S100B analysis was sampled before surgery, at the end of CPB, and then 1, 2, 3, 4, 5, 6, 8, 10, 15, 24 and 48 hours after surgery. The S100B levels at these time points will be referred to as T0, T1, T2....T48. Blood samples, both arterial and venous samples, were cooled and centrifuged within 5 hours. All samples were measured by a monoclonal two-site immunoluminometric assay (Sangtec 100, AB Sangtec Medical, Bromma, Sweden). S100B kinetic calculations Since early levels of S100B are contaminated by S100B from cardiotomy suction, an attempt was made to exclude this S100B from the levels measured one and two hours after surgery. Assuming that all of the measured S100B at the termination of CPB was a contamination, this non-cerebral S100B was eliminated with a half-life of 25 minutes, as illustrated in figure  1a  and  1b . The estimated true levels cleansed from the contamination 1 and 2 hours after the end of surgery were thereby calculated by the formula: Figure 1 1a – Measured S100B release pattern in one patient and the calculated residual levels from the S100B from cardiotomy suction during surgery, a half-life of 25 minutes was used. 1b – Estimated true release, calculated by subtracting the residual levels (from 1a) from measured levels. 1c – Measured levels and estimated true release from one patient with high S100B at T0 and low estimated true release at T1. This patient also had a good neuropsychological outcome. 1d – Measured levels and estimated true release from one patient with low S100B at T0 and high estimated true release at T1. This patient had a bad neuropsychological outcome. where C e  is the estimated true levels of S100B at time t, C t  = the measured concentration of S100B at T1 or T2, C 0  the concentration at the end of CPB, t the time after T0 and t 1/2  the half-life of S100B. We have earlier suggested that the elimination rate could be used as another measure of cerebral release [ 5 ], and the elimination rates of S100B between the end of CPB (T0) and 1 hour later, between T1 and T2, and between T2 and T3 were calculated accordingly. The differences between measured S100B levels at T0 and T1, T0 and T2 were also calculated. Neuropsychological method The patients underwent neuropsychological testing by the same trained neuropsychologist 1–2 days before and 5–7 days after surgery. The tests used were: Mental Control, Figural Memory, Logical Memory (A/B), Visual Reproduction, Rey Auditory/Verbal Learning Test (RAVLT), Trail Making A, Trail Making B, Digit Symbol, Digit Span, Visual Memory Span, Visual Paired Associates II or Verbal Paired Associates I and RAVLT, Delayed Retention. The tests were chosen from the Wechsler Memory Scale-Revised (WMS-R), the Wechsler Adult Intelligence Scale (WAIS – R) and the Halsted-Reitan Neuropsychological Battery [ 20 , 21 ]. Differences for each sub-test were first calculated and then standardized to z-values. All sub-tests were then aggregated to create an impairment index [ 4 ]. The impairment index was a continuous variable, where a positive value reflected an improvement in neuropsychological test and a negative value reflected deterioration. The incidence of neuropsychological impairment in the study group was calculated according to the 1 standard deviation criterion (SD) as defined by Newman and the 20% criterion as defined by Stump [ 22 - 24 ]. Statistical analysis All results were analyzed with the Statistica version 5.0 for PC. Regression analysis was performed with the least square method with a casewise deletion of missing data. For the multiple regression a backwards stepwise regression was performed to determine which variables to include in the final analysis. The initial variables included in this analysis were age, gender, perfusion time, years of education, and S100B levels at all sampling times. A p-value < 0,05 was considered significant. Unless otherwise stated numerical values are presented as mean ± 1 standard deviation.
Methods
Study design The study group comprised 56 patients who underwent coronary artery bypass graft (CABG) surgery at the Division of Cardiac Surgery, University Hospital MAS, Malmoe, Sweden and Department of Cardiothoracic Surgery, Lund University Hospital, Lund, Sweden. Only patients planned for elective CABG with cardiopulmonary bypass (CPB) as their sole procedure were included. The study protocol was approved by the local ethics committee, and patients gave a written informed consent before the study protocol was initiated. Patients with a history of stroke, transient ischemic attack (TIA), reversible neurological disorder (RIND), known carotid artery disease or other brain diseases were excluded. In order to avoid possible influence of renal disorder on the elimination of S100B, patients with known renal failure (Creatinin > 160 μmol/L) were excluded. The patients were examined for signs of neurological dysfunctions daily during the hospital stay by either experienced cardiac anesthesiologists or by experienced cardiac surgeons.
Study design
The study group comprised 56 patients who underwent coronary artery bypass graft (CABG) surgery at the Division of Cardiac Surgery, University Hospital MAS, Malmoe, Sweden and Department of Cardiothoracic Surgery, Lund University Hospital, Lund, Sweden. Only patients planned for elective CABG with cardiopulmonary bypass (CPB) as their sole procedure were included. The study protocol was approved by the local ethics committee, and patients gave a written informed consent before the study protocol was initiated. Patients with a history of stroke, transient ischemic attack (TIA), reversible neurological disorder (RIND), known carotid artery disease or other brain diseases were excluded. In order to avoid possible influence of renal disorder on the elimination of S100B, patients with known renal failure (Creatinin > 160 μmol/L) were excluded.The patients were examined for signs of neurological dysfunctions daily during the hospital stay by either experienced cardiac anesthesiologists or by experienced cardiac surgeons.Perioperative management Anesthesia was induced with midazolam 3–5 mg iv (Dormicum ® , Roche, Basel, Switzerland) or propofol (Diprivan ® , Zeneca Ltd, Cheshire, England) 10 mg/kg. It was subsequently maintained with fentanyl 10 μg/kg (Leptanal ® , Janssen Pharmaceutica, Beerse, Belgien), a continuous infusion of propofol 3–6 mg/kg/h or inhalation of isoflurane 0,5–1% (Forene ® , Abbott Laboratories). Nitrous oxide (Aga Industries, Stockholm, Sweden) was used before CPB but not during or after CPB. CABG surgery was performed during aortic cross clamping with the distal anastomosis preceding the proximal anastomosis. A tangential occluder replaced the cross-clamp during the proximal anastomosis. Antegrade cold S:t Thomas crystalloid cardioplegia was used (Cardioplegi ® , Pharmacia-Upjohn, Uppsala, Sweden) and administered in the ascending aorta and the anastomosed vein-grafts intermittently. Perfusion was performed with a roller pump (Cobe Industries, Denver, Colorado, USA). The perfusion catheters and circuit were made of polyvinylchloride in the line and silicon in the pumphead. The arterial cannulation was made in the ascending aorta and venous cannulation in the right atrium by a two-stage venous cannula. All circuits contained a heparin-coated 40 μm arterial filter (Cobe Sence, Cobe Industries) and a membrane oxygenator (Cobe Duo oxygenator, Cobe Industries). The circuit was primed with approximately 1000 ml of Ringer's lactate (Pharmacia-Upjohn), 250 ml 15% Mannitol (Pharmacia-Upjohn) and 75 mmol Addex tromethamine (Pharmacia-Upjohn). Perfusion flow was non-pulsatile with a flow rate of 2.4 l/min/m 2  at normothermia. The perfusate was cooled to approximately 32°C. Heparin (400 U/kg bodyweight) was given prior to cannulation and reversed with equal doses of protamine sulphate at decannulation. After surgery, the patients patient were transferred to the ICU for recovery and enrolled in the sampling scheme for S100B analysis. None of the patients received autotransfusion.
Perioperative management
Anesthesia was induced with midazolam 3–5 mg iv (Dormicum ® , Roche, Basel, Switzerland) or propofol (Diprivan ® , Zeneca Ltd, Cheshire, England) 10 mg/kg. It was subsequently maintained with fentanyl 10 μg/kg (Leptanal ® , Janssen Pharmaceutica, Beerse, Belgien), a continuous infusion of propofol 3–6 mg/kg/h or inhalation of isoflurane 0,5–1% (Forene ® , Abbott Laboratories). Nitrous oxide (Aga Industries, Stockholm, Sweden) was used before CPB but not during or after CPB.CABG surgery was performed during aortic cross clamping with the distal anastomosis preceding the proximal anastomosis. A tangential occluder replaced the cross-clamp during the proximal anastomosis. Antegrade cold S:t Thomas crystalloid cardioplegia was used (Cardioplegi ® , Pharmacia-Upjohn, Uppsala, Sweden) and administered in the ascending aorta and the anastomosed vein-grafts intermittently.Perfusion was performed with a roller pump (Cobe Industries, Denver, Colorado, USA). The perfusion catheters and circuit were made of polyvinylchloride in the line and silicon in the pumphead. The arterial cannulation was made in the ascending aorta and venous cannulation in the right atrium by a two-stage venous cannula. All circuits contained a heparin-coated 40 μm arterial filter (Cobe Sence, Cobe Industries) and a membrane oxygenator (Cobe Duo oxygenator, Cobe Industries). The circuit was primed with approximately 1000 ml of Ringer's lactate (Pharmacia-Upjohn), 250 ml 15% Mannitol (Pharmacia-Upjohn) and 75 mmol Addex tromethamine (Pharmacia-Upjohn). Perfusion flow was non-pulsatile with a flow rate of 2.4 l/min/m 2  at normothermia. The perfusate was cooled to approximately 32°C. Heparin (400 U/kg bodyweight) was given prior to cannulation and reversed with equal doses of protamine sulphate at decannulation.After surgery, the patients patient were transferred to the ICU for recovery and enrolled in the sampling scheme for S100B analysis. None of the patients received autotransfusion.S100-protein analysis and calculations Serum for S100B analysis was sampled before surgery, at the end of CPB, and then 1, 2, 3, 4, 5, 6, 8, 10, 15, 24 and 48 hours after surgery. The S100B levels at these time points will be referred to as T0, T1, T2....T48. Blood samples, both arterial and venous samples, were cooled and centrifuged within 5 hours. All samples were measured by a monoclonal two-site immunoluminometric assay (Sangtec 100, AB Sangtec Medical, Bromma, Sweden).
S100-protein analysis and calculations
Serum for S100B analysis was sampled before surgery, at the end of CPB, and then 1, 2, 3, 4, 5, 6, 8, 10, 15, 24 and 48 hours after surgery. The S100B levels at these time points will be referred to as T0, T1, T2....T48. Blood samples, both arterial and venous samples, were cooled and centrifuged within 5 hours. All samples were measured by a monoclonal two-site immunoluminometric assay (Sangtec 100, AB Sangtec Medical, Bromma, Sweden).S100B kinetic calculations Since early levels of S100B are contaminated by S100B from cardiotomy suction, an attempt was made to exclude this S100B from the levels measured one and two hours after surgery. Assuming that all of the measured S100B at the termination of CPB was a contamination, this non-cerebral S100B was eliminated with a half-life of 25 minutes, as illustrated in figure  1a  and  1b . The estimated true levels cleansed from the contamination 1 and 2 hours after the end of surgery were thereby calculated by the formula: Figure 1 1a – Measured S100B release pattern in one patient and the calculated residual levels from the S100B from cardiotomy suction during surgery, a half-life of 25 minutes was used. 1b – Estimated true release, calculated by subtracting the residual levels (from 1a) from measured levels. 1c – Measured levels and estimated true release from one patient with high S100B at T0 and low estimated true release at T1. This patient also had a good neuropsychological outcome. 1d – Measured levels and estimated true release from one patient with low S100B at T0 and high estimated true release at T1. This patient had a bad neuropsychological outcome. where C e  is the estimated true levels of S100B at time t, C t  = the measured concentration of S100B at T1 or T2, C 0  the concentration at the end of CPB, t the time after T0 and t 1/2  the half-life of S100B. We have earlier suggested that the elimination rate could be used as another measure of cerebral release [ 5 ], and the elimination rates of S100B between the end of CPB (T0) and 1 hour later, between T1 and T2, and between T2 and T3 were calculated accordingly. The differences between measured S100B levels at T0 and T1, T0 and T2 were also calculated.
S100B kinetic calculations
Since early levels of S100B are contaminated by S100B from cardiotomy suction, an attempt was made to exclude this S100B from the levels measured one and two hours after surgery. Assuming that all of the measured S100B at the termination of CPB was a contamination, this non-cerebral S100B was eliminated with a half-life of 25 minutes, as illustrated in figure  1a  and  1b . The estimated true levels cleansed from the contamination 1 and 2 hours after the end of surgery were thereby calculated by the formula:where C e  is the estimated true levels of S100B at time t, C t  = the measured concentration of S100B at T1 or T2, C 0  the concentration at the end of CPB, t the time after T0 and t 1/2  the half-life of S100B.We have earlier suggested that the elimination rate could be used as another measure of cerebral release [ 5 ], and the elimination rates of S100B between the end of CPB (T0) and 1 hour later, between T1 and T2, and between T2 and T3 were calculated accordingly. The differences between measured S100B levels at T0 and T1, T0 and T2 were also calculated.Neuropsychological method The patients underwent neuropsychological testing by the same trained neuropsychologist 1–2 days before and 5–7 days after surgery. The tests used were: Mental Control, Figural Memory, Logical Memory (A/B), Visual Reproduction, Rey Auditory/Verbal Learning Test (RAVLT), Trail Making A, Trail Making B, Digit Symbol, Digit Span, Visual Memory Span, Visual Paired Associates II or Verbal Paired Associates I and RAVLT, Delayed Retention. The tests were chosen from the Wechsler Memory Scale-Revised (WMS-R), the Wechsler Adult Intelligence Scale (WAIS – R) and the Halsted-Reitan Neuropsychological Battery [ 20 , 21 ]. Differences for each sub-test were first calculated and then standardized to z-values. All sub-tests were then aggregated to create an impairment index [ 4 ]. The impairment index was a continuous variable, where a positive value reflected an improvement in neuropsychological test and a negative value reflected deterioration. The incidence of neuropsychological impairment in the study group was calculated according to the 1 standard deviation criterion (SD) as defined by Newman and the 20% criterion as defined by Stump [ 22 - 24 ].
Neuropsychological method
The patients underwent neuropsychological testing by the same trained neuropsychologist 1–2 days before and 5–7 days after surgery. The tests used were: Mental Control, Figural Memory, Logical Memory (A/B), Visual Reproduction, Rey Auditory/Verbal Learning Test (RAVLT), Trail Making A, Trail Making B, Digit Symbol, Digit Span, Visual Memory Span, Visual Paired Associates II or Verbal Paired Associates I and RAVLT, Delayed Retention. The tests were chosen from the Wechsler Memory Scale-Revised (WMS-R), the Wechsler Adult Intelligence Scale (WAIS – R) and the Halsted-Reitan Neuropsychological Battery [ 20 , 21 ].Differences for each sub-test were first calculated and then standardized to z-values. All sub-tests were then aggregated to create an impairment index [ 4 ]. The impairment index was a continuous variable, where a positive value reflected an improvement in neuropsychological test and a negative value reflected deterioration. The incidence of neuropsychological impairment in the study group was calculated according to the 1 standard deviation criterion (SD) as defined by Newman and the 20% criterion as defined by Stump [ 22 - 24 ].Statistical analysis All results were analyzed with the Statistica version 5.0 for PC. Regression analysis was performed with the least square method with a casewise deletion of missing data. For the multiple regression a backwards stepwise regression was performed to determine which variables to include in the final analysis. The initial variables included in this analysis were age, gender, perfusion time, years of education, and S100B levels at all sampling times. A p-value < 0,05 was considered significant. Unless otherwise stated numerical values are presented as mean ± 1 standard deviation.
Statistical analysis
All results were analyzed with the Statistica version 5.0 for PC. Regression analysis was performed with the least square method with a casewise deletion of missing data. For the multiple regression a backwards stepwise regression was performed to determine which variables to include in the final analysis. The initial variables included in this analysis were age, gender, perfusion time, years of education, and S100B levels at all sampling times. A p-value < 0,05 was considered significant. Unless otherwise stated numerical values are presented as mean ± 1 standard deviation.Results Patient demographics are presented in table  1 . None of the patients suffered a clinically detectable stroke. The incidence of neuropsychological impairment was 37,5% (n = 21, 95% C.I 26,0–50,6%) according to the 1 standard deviation criterion, and 80,4% (n = 45, 95% C.I. 68,1–88,6%) according to the 20% criterion. Table 1 Demographics for the study group. Mean St. dev. Number 56 Sex (M/F) 47/9 Age (years) 60.4 9.0 Education (years) 9.6 3.1 Perfusion time (Minutes) 82.8 31.5 X-clamp (minutes) 53.9 23.5 The appearance of S100B protein followed the same pattern in all patients with high levels at the end of CPB and a decrease or slight increase the first hour (figure  2 ). Thereafter a subsequent decrease was observed during the rest of the study period, except in one patient in whom the concentration of S100B increased to 2,0 μg/L 48 hours after surgery. Mean estimated true release of S100B, calculated according to equation [ 1 ], was lower at T1 and T2 compared to measured S100B levels (1.43 ± 1.37 μg/L vs. 2.11 ± 1.81 μg/L and 1.22 ± 1.10 μg/L vs. 1.32 ± 1.17 μg/L). Three representative examples of this calculation are shown in figure  1b ,  1c  and  1d . Figure 2 S100B release pattern after cardiac surgery with cardiopulmonary bypass shown as a boxplot. We found a correlation between patient age and S100B levels measured up to 24 hours after bypass (Table  2 ). No significant correlation was found between measured S100B levels at the sampling times and neuropsychological impairment in simple regression analysis (Table  3 ). Neither did age, years of education and duration of perfusion correlate with neuropsychological impairment when tested in simple regression analysis (Table  3 ). Table 2 The relation between S100B levels and patient age tested in univariate linear regression analysis. r-value p-level S100B at T0 0.19 n. s S100B at T1 0.30 <0.05 S100B at T2 0.30 <0.05 S100B at T3 0.34 <0.05 S100B at T4 0.37 <0.05 S100B at T5 0.32 <0.05 S100B at T6 0.37 <0.05 S100B at T8 0.38 <0.01 S100B at T10 0.42 <0.005 S100B at T15 0.36 <0.05 S100B at T24 0.46 <0.005 S100B at T48 0.004 n.s Table 3 The relation between S100B levels, demographic variables and neuropsychological impairment index, expressed as r-value from linear regression analysis (* = p < 0.05). Mean (± SD) S100B levels are also presented. (Est. true release = estimated true release when residual levels from contamination have been excluded) Mean ± St.dev. r-value S100B at T0 3.63 ± 2.84 0.08 S100B at T1 2.11 ± 1.81 -0.16 S100B at T2 1.32 ± 1.17 -0.11 S100B at T3 0.87 ± 0.73 -0.12 S100B at T4 0.60 ± 0.42 -0.06 S100B at T5 0.49 ± 0.38 -0.12 S100B at T6 0.42 ± 0.33 -0.15 S100B at T8 0.38 ± 0.25 -0.12 S100B at T10 0.31 ± 0.21 -0.06 S100B at T15 0.25 ± 0.16 -0.09 S100B at T24 0.21 ± 0.11 -0.10 S100B at T48 0.21 ± 0.27 -0.09 Est. true release at T1 1.43 ± 1.37 -0.22 Est. true residual at T2 1.22 ± 1.10 -0.12 Elimination rate T0-T1 0.50 ± 0.46 0.26 Elimination rate T1-T2 0.48 ± 0.25 -0.05 Elimination rate T2-T3 0.68 ± 0.32 -0.12 Difference T0-T1 1.53 ± 1.66 0,30* Difference T0-T2 2.31 ± 2.01 0,18 Age 0.16 Education -0.06 Perfusion time 0.12 In multiple regression analysis, measured S100B levels at the end of CPB (T0), one hour later (T1) and age were found to explain part of the neuropsychological impairment (r = 0.49, p < 0.005, Table  4 ). It is worth noting that the correlation was positive at T0 and negative at T1, implicating a better outcome if S100B was high at T0 and worse if the levels were high at T1. Age had a negative correlation. Furthermore the combination of age, S100B at T0 and S100B at either T3 or T6 gave significant correlations in the same manner (r = 0.41, p < 0.05 and r = 0.42, p < 0.05 respectively). The difference between S100B levels at T0 and T1 was found to correlate positively with neuropsychological outcome (Table  3 ). No correlation was found when the estimated true release of S100B was tested against neuropsychological outcome, neither did the elimination rate fall out significantly in simple regression analysis (Table  3 ). Table 4 The results of the backwards stepwise multiple regression analysis model to explain the neuropsychological impairment index (r = 0.49, p < 0.005). Variable Partial correlation Beta p-value S100 at T0 0.45 0.845 <0.005 S100 at T1 -0.47 -0.939 <0.001 Age 0.31 0.307 <0.05 Regression <0.005
Results
Patient demographics are presented in table  1 . None of the patients suffered a clinically detectable stroke. The incidence of neuropsychological impairment was 37,5% (n = 21, 95% C.I 26,0–50,6%) according to the 1 standard deviation criterion, and 80,4% (n = 45, 95% C.I. 68,1–88,6%) according to the 20% criterion.Demographics for the study group.The appearance of S100B protein followed the same pattern in all patients with high levels at the end of CPB and a decrease or slight increase the first hour (figure  2 ). Thereafter a subsequent decrease was observed during the rest of the study period, except in one patient in whom the concentration of S100B increased to 2,0 μg/L 48 hours after surgery. Mean estimated true release of S100B, calculated according to equation [ 1 ], was lower at T1 and T2 compared to measured S100B levels (1.43 ± 1.37 μg/L vs. 2.11 ± 1.81 μg/L and 1.22 ± 1.10 μg/L vs. 1.32 ± 1.17 μg/L). Three representative examples of this calculation are shown in figure  1b ,  1c  and  1d .We found a correlation between patient age and S100B levels measured up to 24 hours after bypass (Table  2 ). No significant correlation was found between measured S100B levels at the sampling times and neuropsychological impairment in simple regression analysis (Table  3 ). Neither did age, years of education and duration of perfusion correlate with neuropsychological impairment when tested in simple regression analysis (Table  3 ).The relation between S100B levels and patient age tested in univariate linear regression analysis.The relation between S100B levels, demographic variables and neuropsychological impairment index, expressed as r-value from linear regression analysis (* = p < 0.05). Mean (± SD) S100B levels are also presented. (Est. true release = estimated true release when residual levels from contamination have been excluded)In multiple regression analysis, measured S100B levels at the end of CPB (T0), one hour later (T1) and age were found to explain part of the neuropsychological impairment (r = 0.49, p < 0.005, Table  4 ). It is worth noting that the correlation was positive at T0 and negative at T1, implicating a better outcome if S100B was high at T0 and worse if the levels were high at T1. Age had a negative correlation. Furthermore the combination of age, S100B at T0 and S100B at either T3 or T6 gave significant correlations in the same manner (r = 0.41, p < 0.05 and r = 0.42, p < 0.05 respectively). The difference between S100B levels at T0 and T1 was found to correlate positively with neuropsychological outcome (Table  3 ). No correlation was found when the estimated true release of S100B was tested against neuropsychological outcome, neither did the elimination rate fall out significantly in simple regression analysis (Table  3 ).The results of the backwards stepwise multiple regression analysis model to explain the neuropsychological impairment index (r = 0.49, p < 0.005).Discussion This study presents some interesting findings that may be relevant in clinical practice. There is a clear relation between patient age and release of S100B up to 24 hours after cardiac surgery. This correlation is strong and not influenced by the perioperative contamination of S100B caused by the use of coronary suction [ 4 ]. The univariate analysis did not provide a clear answer to the question whether there is a relationship between neuropsychological outcome and S100B release. However, from table  3  it is worth noting that the r-values in univariate regression analysis are negative at all sampling points except at T0 (immediately after bypass). The consistent finding of a negative correlation 1 hour and onwards after bypass is intriguing and warrants further exploration. The multiple regression analysis resulted in a significant correlation between neuropsychological deterioration and the three variables: S100B at T0, S100B at T1 and patient age. The r-value in the multiple regression analysis was 0.49, which evokes the question why the multiple regression is stronger than the univariate regression. One possible explanation could be that by including the S100B level at the end of CPB we compensate for some part of the contamination in the S100B levels one hour after surgery. Age correlated also with outcome. As expected, the older the patient the higher the risk for neuropsychological deterioration, which is in accordance to the fact that age is a risk factor for decline in neuropsychological tests after surgery [ 23 ]. Our results are to some extent in concordance with other reports in this field. Two groups have reported no relation between S100B and neuropsychological test results, [ 2 , 18 ] and two groups have found a relation using a composite S100B end-point [ 3 , 4 ]. Only one of these studies was designed to exclude the extracerebral inflow of S100B [ 18 ]. These contradicting findings support our notion that S100B kinetics after cardiac surgery are complicated. Interestingly, in the multiple regression analysis there was a positive correlation between S100B levels at T0 and outcome, a finding that stands in contrast to the hypothesis that S100B could be used as serum marker for cognitive dysfunction. This finding is especially interesting since most of the measure S100B at T0 is contamination. In an earlier study we found that approximately 80% of measured S100B at this point is from extracerebral sources in CABG patients [ 4 ]. We offer no explanation for this unexpected finding, but it is intriguing and calls for further investigations. When interpreting the results of our study, as well as comparing them with those of other reports, several issues need to be addressed. To begin with the origin of S100B measured after CPB is not exclusively cerebral. From our previous study as well as from reports by Anderson et al [ 25 ], it is clear that shed blood in the mediastinum contains very high levels of S100B. When this blood is retransfused either directly by cardiotomy suction or later in the course by autotransfusion during the postoperative care, the systemic levels of S100B are affected. The source of this S100B is non-cerebral, probably from S100B containing tissue such as fat, skin and bone marrow. No autotransfusion was used in this study, however reabsorbtion of S100B from injured fat tissue may contribute to the measured serum levels of S100B. Since we previously have been able to determine the half life of S100B in blood to be 25 min, it was possible to control for the peri-operative contribution from cardiotomy suctions by using the equation mentioned to obtain the estimated true release at T1 and T2. When these values were entered in simple regression analysis, no correlation was found to neuropsychological outcome. However, if multiple regression analysis was used, a positive correlation was found, these results were identical to those obtained with the measured S100B values, and therefore we can conclude that the use of the correction procedure represented by the equation does not contribute to the evaluation of the results. Moreover, we should be careful to overinterpret the significance of correlations in a study of relatively few patients and several end-points, i.e sampling times for S100B. There is always a risk of accepting a false hypothesis. Preferably, a study of this sort should contain a large number of patients and only one or few end-points. However, the aim of this study was to clarify the complex kinetics of early S100B release and its possible connection to a neuropsychological decline, not to determine the perfect use of S100b for detecting neuropsychological outcome after cardiac surgery. In the mathematical correction model suggested here, we assume that all S100B measured at T0 is of extrecerebral origin. This is of course not the case, but we do not know the relation between cerebral and extracerebral S100B at this time-point in each individual. By assuming that none of the S100B measured at T0 is of cerebral origin, we can be sure that our mathematical model does not include non-cerebral S100B at T1 and later. However, these levels might be lower than the true levels of cerebral S100B since we could have excluded cerebral S100B present at T0. This could also be an explanation that the multiple regression analysis showed stronger correlations. One important issue, which must be considered in this type of study, is the strength that can be expected in the correlation between two different measures of brain function. The functional domains in the brain covered by neuropsychological tests vary depending on the tests used and are by no means complete in any test battery. By the same reasoning, the magnitude of a possible cerebral release of S100B after an injury may vary according to the severity of the insult as well as the location of the insult, since glia dense areas express more S100B than others [ 26 ].
Discussion
This study presents some interesting findings that may be relevant in clinical practice. There is a clear relation between patient age and release of S100B up to 24 hours after cardiac surgery. This correlation is strong and not influenced by the perioperative contamination of S100B caused by the use of coronary suction [ 4 ].The univariate analysis did not provide a clear answer to the question whether there is a relationship between neuropsychological outcome and S100B release. However, from table  3  it is worth noting that the r-values in univariate regression analysis are negative at all sampling points except at T0 (immediately after bypass). The consistent finding of a negative correlation 1 hour and onwards after bypass is intriguing and warrants further exploration.The multiple regression analysis resulted in a significant correlation between neuropsychological deterioration and the three variables: S100B at T0, S100B at T1 and patient age. The r-value in the multiple regression analysis was 0.49, which evokes the question why the multiple regression is stronger than the univariate regression. One possible explanation could be that by including the S100B level at the end of CPB we compensate for some part of the contamination in the S100B levels one hour after surgery.Age correlated also with outcome. As expected, the older the patient the higher the risk for neuropsychological deterioration, which is in accordance to the fact that age is a risk factor for decline in neuropsychological tests after surgery [ 23 ].Our results are to some extent in concordance with other reports in this field. Two groups have reported no relation between S100B and neuropsychological test results, [ 2 , 18 ] and two groups have found a relation using a composite S100B end-point [ 3 , 4 ]. Only one of these studies was designed to exclude the extracerebral inflow of S100B [ 18 ]. These contradicting findings support our notion that S100B kinetics after cardiac surgery are complicated.Interestingly, in the multiple regression analysis there was a positive correlation between S100B levels at T0 and outcome, a finding that stands in contrast to the hypothesis that S100B could be used as serum marker for cognitive dysfunction. This finding is especially interesting since most of the measure S100B at T0 is contamination. In an earlier study we found that approximately 80% of measured S100B at this point is from extracerebral sources in CABG patients [ 4 ]. We offer no explanation for this unexpected finding, but it is intriguing and calls for further investigations.When interpreting the results of our study, as well as comparing them with those of other reports, several issues need to be addressed. To begin with the origin of S100B measured after CPB is not exclusively cerebral. From our previous study as well as from reports by Anderson et al [ 25 ], it is clear that shed blood in the mediastinum contains very high levels of S100B. When this blood is retransfused either directly by cardiotomy suction or later in the course by autotransfusion during the postoperative care, the systemic levels of S100B are affected. The source of this S100B is non-cerebral, probably from S100B containing tissue such as fat, skin and bone marrow. No autotransfusion was used in this study, however reabsorbtion of S100B from injured fat tissue may contribute to the measured serum levels of S100B.Since we previously have been able to determine the half life of S100B in blood to be 25 min, it was possible to control for the peri-operative contribution from cardiotomy suctions by using the equation mentioned to obtain the estimated true release at T1 and T2. When these values were entered in simple regression analysis, no correlation was found to neuropsychological outcome. However, if multiple regression analysis was used, a positive correlation was found, these results were identical to those obtained with the measured S100B values, and therefore we can conclude that the use of the correction procedure represented by the equation does not contribute to the evaluation of the results. Moreover, we should be careful to overinterpret the significance of correlations in a study of relatively few patients and several end-points, i.e sampling times for S100B. There is always a risk of accepting a false hypothesis. Preferably, a study of this sort should contain a large number of patients and only one or few end-points. However, the aim of this study was to clarify the complex kinetics of early S100B release and its possible connection to a neuropsychological decline, not to determine the perfect use of S100b for detecting neuropsychological outcome after cardiac surgery.In the mathematical correction model suggested here, we assume that all S100B measured at T0 is of extrecerebral origin. This is of course not the case, but we do not know the relation between cerebral and extracerebral S100B at this time-point in each individual. By assuming that none of the S100B measured at T0 is of cerebral origin, we can be sure that our mathematical model does not include non-cerebral S100B at T1 and later. However, these levels might be lower than the true levels of cerebral S100B since we could have excluded cerebral S100B present at T0. This could also be an explanation that the multiple regression analysis showed stronger correlations.One important issue, which must be considered in this type of study, is the strength that can be expected in the correlation between two different measures of brain function. The functional domains in the brain covered by neuropsychological tests vary depending on the tests used and are by no means complete in any test battery. By the same reasoning, the magnitude of a possible cerebral release of S100B after an injury may vary according to the severity of the insult as well as the location of the insult, since glia dense areas express more S100B than others [ 26 ].Conclusions In conclusion, with the present knowledge, a single S100B sampled in the postoperative course after cardiac surgery can not be of use in clinical practice in order to predict neuropsychological outcome with an acceptable sensitivity. However, utilizing a statistic model, an association between S100B levels the first hours after surgery and neuropsychological outcome was found, where the most informative time point seems to be 1 hour after the termination of CPB. The controversial significance of an increased S100B immediately after surgery is indeed intriguing and it inspires further studies of the mechanisms of S100B release after cardiac surgery as well as other fields of brain damage.
Conclusions
In conclusion, with the present knowledge, a single S100B sampled in the postoperative course after cardiac surgery can not be of use in clinical practice in order to predict neuropsychological outcome with an acceptable sensitivity.However, utilizing a statistic model, an association between S100B levels the first hours after surgery and neuropsychological outcome was found, where the most informative time point seems to be 1 hour after the termination of CPB.The controversial significance of an increased S100B immediately after surgery is indeed intriguing and it inspires further studies of the mechanisms of S100B release after cardiac surgery as well as other fields of brain damage.Competing interests The author(s) declare that they have no competing interests.
Competing interests
The author(s) declare that they have no competing interests.Authors' contributions HJ: Principal investigator recruited, enrolled patients analyzed and wrote the paper PJ: Had an integral role in the planning and the analysis, also help with writing MB: Designed neuropsychological test battery. Analyzed neuropsychological data CB: Performed all neuropsychological testing with patients CA: Did the S100B-analyzes SB: Mentor an principal leader of the project, who also helped with the writing.
Authors' contributions
HJ: Principal investigator recruited, enrolled patients analyzed and wrote the paperPJ: Had an integral role in the planning and the analysis, also help with writingMB: Designed neuropsychological test battery. Analyzed neuropsychological dataCB: Performed all neuropsychological testing with patientsCA: Did the S100B-analyzesSB: Mentor an principal leader of the project, who also helped with the writing.Pre-publication history The pre-publication history for this paper can be accessed here:
Pre-publication history
The pre-publication history for this paper can be accessed here: