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The role of CD4+ T lymphocytes in elaborating cytokine response in multiply injured patients
Proceedings
of the British
Trauma
Society
To date we have treated seven patients with fractures above total knee replacements using the Richards supracondylar femoral nail (Smith and Nephew Richards, Memphis, TN). This offers the advantages of reliable fracture fixation and minimum soft-tissue dissection. All the patients were women, mean age 69.5 years (39-85 years). Average time from total knee replacement to fracture was 3.3 years (3 days to 11 years). Mean time to union was 15.7 weeks (12-20 weeks) and mean follow up was 13.4 months (6-24 months). There were no significant post-operative complications and all but one patient achieved their previous level of mobility. The supracondylar femoral nail offers several advantages over other treatment modalities. The procedure can be performed through previous incisions,operative time is generally reduced and anatomical alignment is often more readily achieved. Extensive soft tissue dissection is unnecessaryso reducing the risks of non-union and infection. Furthermore, protected weight bearing can often be commencedearly. Whilst further evaluation is required, the supracondylar femoral nail may becomethe treatment ef choice for most fractures proximal to total knee replacements. J. Keenan, G. Chakrabarty and J.H. Newman (Bristol, UK) Treatmentof supracondylar femoral fracture above a fatal knee replacement by revision fo a custom made hinged prosthesis
Supracondylar fracture above a total knee arthroplasty (TKA) is a devastating complication for both patient and surgeon. Various methods of treatment are available including non-operative treatment, open reduction and internal fixation, external fixation, retrograde intramedullary nailing, intramedullary Rush pin fixation and revision arthroplasty. We have used a custom-made Endo-Model rotational knee prosthesis to treat seven casesof displaced supracondylar fracture above a total knee arthroplasty. The average age of the patients was 78 years and their average weight was 90 kg. The original prostheseshad been irt situ for between 4 weeks and 8 years. Two patients had primary internal fixation of the fracture which failed with a non-union at the fracture site, one patient had a tibia1 Steinman pin inserted for skeletal traction and four had immediate revision. All patients made a rapid post-operative recovery being mobile with the use of simple walking aids after 7 days and dischargedfrom hospital after an average of 3 weeks, The averagefollow-up period of these patients is 9 months. Unfortunately the patient who had a tibia1 Steinman pin inserted pre-operatively developed deep sepsisrequiring subsequentremoval of the prosthesis.At latest assessment four patients have had a good or excellent outcome as measured by the Bristol Knee Score. Two patients with recently inserted prostheseshave a fair result to date and continue to improve. Our experience demonstrates that the use of this custom-made implant to treat displaced supracondylar fractures above a TKA achieves good implant alignment, fixation and stability whilst allowing rapid recovery and mobilization. No long-term follow up is yet available but a quick return to pre-injury state is of particular benefit to elderly osteoporotic patients in whom these difficult fractures usually occur. The cost savingsof earlier mobilization and discharge serve to offset the high cost of the prosthesis.The technique should probably be reserved for
239
low fractures in which fixation is technically challenging or for failure of internal fixation. N. Cassidy, M. F&gibbon, C. Condron and R. Moran (Dublin, Ireland) Interleukind production in lower limb trauma
Interleukin-6 (IL-6) is a cytokine which is regarded as an early and integral mediator of the inflammatory response to trauma. Elevated systemic levels are demonstrated within hours of blunt injury and surgical procedures.This cytokine hasbeen implicated in the priming of neutrophils, the development of adult respiratory distress syndrome (ARDS) and multi-organ failure (MOF). Early and persistent high levels are associatedwith a poorer prognosis. Long-bone fractures, especiallyfemoral fractures are associated with an increased risk of systemic complications including ARDS and MOF. Little attention has been given to the contribution of lower-limb trauma which includes long-bone fractures to the systemicinflammatory load. We withdrew femoral artery and femoral vein blood samplesfrom 10 patients who came to theatre for surgical procedures on femoral or tibia1 shaft fractures. The serum was then analysed using an enzyme linked immunosorbent assayfor IL-6 levels. We found that the IL-6 level in the vein was usually twice the arterial level in each patient. There was no strong correlation with the Injury Severity Score or the time interval from injury to surgery. These preliminary results indicate that the injured limb with a long-bone fracture may be a significant source of IL-6. This study also shows that in measuring cytokine levels in trauma patients the site of blood sampling should be stated and consistentas there are significant differences in blood from different sites at identical times in these patients. M. Fitzgibbon, H.P. Redmond and R. Moran (Dublin, Ireland) The role of CD4+ T lymphocytes in elaborating cyfokine response in multiply injured patients
Few disorders can compete with sepsis as a major contributor to morbidity and mortality among seriously injured patients. A vast network of cytokines and other immunologicalfactors are fundamental to the mediation of sepsisand its sequelae.Trauma-relatedimmune responseis a mixed complex of events in which overstimulation and depressedfunction are coupled, leaving the injured patient susceptibleto serious infection. In a seriesof 100 injured patients with ISS> 21 we demonstrated that exaggerated releaseof polymorphonuclear neutrophils (PMNs) associated with significant lymphopenia occurs rapidly after severe injury and correlateswith poor outcome and sepsis development. The specificity of the immune responseis due to lymphocytes which makesthis significant lymphopenia an important event in the period post injury. The proposed division of cytokine-producing T lymphocytes into T helper 1 (Thl) and Th2 subsetswith profoundly different membrane proteins and functions, is currently a key issuein regulation of immune response.Theseproteins serve as phenotypic markers of lymphocyte subsets;CD4 is expressed predominantly on helper cells and CD8 on cytotoxic T cells. The exact mechanismwhich drives naive CD4’ T cells in either direction is unclear. Interleukin 12 (IL-12) a 70 kD heterodimer produced by activated monocytes and B cells,is believed to stimulate the differentiation of T helper cells to a predominantly Thl response.The ability of macrophagesand lymphocytes to stimulate each
240
Injury:
International
others’ functions provides an important amplification processfor specificimmunity, which may be lost following severeinjury. In a seriesof trauma patients (N = 6, ISS> Zl), we report the pattern of the Thl/Th2 cytokine model to be altered with decreasedplasma IFN-1/ and IL-2 on one hand, and elevated IL-10 on the other, measuredby specific immunoassaysand compared with age-matched normal controls. We also report significantly decreasedproduction of IL-12 after injury using a highly sensitive p70 specific monoclonal antibody sandwich ELISA immunoassay. This cytokine pattern represents an inert Thl responsein the post-traumatic phase, however this may be related to activation-induced cell death or apoptosisof CD4+ T cells, rather than a switch to Th2. We therefore investigated CD4/CD8ratios and lymphocyte apoptosis.Resultsdemonstrate alterations in CD4/CDS ratios following acute injury and particularly during septic episodes.Using flow cytometry PMN respiratory burst was found to be decreased and correlated well with clinical manifestationsof sepsis and was thus incorporated into the criteria for defining septic episodes.Low ratios of CD4+ T lymphocytes were associatedwith notable decreasein respiratory burst. Fas (CD95), a cell surface protein belonging to the tumour necrosisfactor (TNF) receptor family, is expressedpredominantly on activated T cells and hasbeen shown to bind to Fas ligand (FasL) resulting in target cell apoptosis. We therefore studied Fas-mediated lymphocyte apoptosis in acute severe injury and report preliminary results of increasedexpressionof CD95using flow cytometry. In conclusion, these results show the importance of the significant lymphopenia observed after injury and suggest that CD4+ Thl anergy in the post-traumatic phasemay be due to preferential activation of subpopulations of CD4’ helper T cellsby activated macrophages,OYto Fas-mediated CD4’ T lymphocyte apoptosis,or to impairment of monocyte-T cell interaction with decreased IL-12 resulting in production of distinct setsof cytokines which have discrete effector functions. M.E. Lovell, S. Sharma, S. Allcock and S.K. Hardy (Blackbum, UK) Insertion site for tibial nails, the continuing story
Recentwork has suggestedthat a patella splitting approach for insertion of intramedullary tibia1nailsis associatedwith an increasedincidence of anterior knee pain. We looked at 48 patients with tibia1fractures stabilized with intramedullary nails. Four nails were unreamed, the rest reamed. Thirty-five fractures were closed,eight Gustilo type I, three type II and two type III. Information about insertion approach and knee pain was available for 38 patients. Fifty per cent had anterior knee pain, 22 had a medial approach performed of whom 12 had pain, 16 had a patella tendon splitting approach of whom seven had pain (NS, x2= 0.43). Suitable X-rays were available to allow measurement of patella tendon shortening in 30 patients (patella included on X-ray view). This demonstrated patella tendon shortening of 2.8 per cent in the pain group (N = 14), 3.4 per cent in the no pain group (N = 16); 3.3 per cent in the split group (N = lo), 3.5 per cent in the medial approach group (N = 17, information on surgical approach not available for three patients). The range of shortening for all patients did not exceed 10 per cent. Literature suggeststhat patella tendon shortening can occur with excessive dissection required for a medial approach at this area of the knee. We
Journal
of the Care of the Injured
Vol. 28, No. 3,1997
agree with recent comments that a controlled trial is required to evaluate this problem further. D.F. McGeehan, F. Richardson, A. Newton and S. Bowers (Stafford, UK and Newport, UK) Training needs and preferences in the Ambulance Service of the United Kingdom
Paramedic training has improved greatly in the last 15 years largely due to the personal commitment of many doctors who have given freely of their time. In 1984, extended training for ambulancepersonnelwas introduced by the National Health Service Training Directorate (NHSTD) which has been at the forefront of teaching. In 1995most Ambulance Authorities achieved the target of a paramedicon every front-line ambulance.The commitment and training of paramedicsin the UK falls far behind those in other countries. In North America, paramedicstrain for over 3000h, becomeadept in advanced life support skills, drug administration and also work closely with Emergency departments. In South Africa, the critical care assistant obtains specialist registration with the South African Medical and Dental Council after the successfulcompletion of a 3 year course. Other countries, including Germany, Australia and Canada have considerably more financial investment in pre-hospital care. In the UK, paramedics are very keen to extend their training and expertise, freely giving up their time to attend courses. A questionnairewas sent to 210 paramedicsrequesting information on their interest in further training. There were 91 (46per cent) replies;96.77per cent were in favour of further training and 77.41per cent were of the opinion that further training should lead to professionalqualifications. That training provision should take the form of a regular daytime lecture/workshop was the preferred option in 66.6per cent. The training areaswhich were thought to be of high importance were Advanced Trauma Life Support (ATLS) (91.4 per cent), Advanced Cardiac Life Support (ACLS) (90.3 per cent) and Advanced Paediatric Life Support (APLS) (83.8per cent). Thosequestionedwere very keen to be taught practical proceduresincluding cricothyroidotomy (43 per cent), needle pleurocentesis (64.5 per cent) and interosseousaccess(47.3per cent). In responseto the question on trauma scoring,only 19.4 per cent thought it to be of high importance and 23.7 per cent thought it to be low in the list of teaching priorities. This is of vital importance to those who are consideringthe implementation of trauma systemsas it is vital to get the patient to the right place at the right time. A questionnaire on tertiary education for paramedic studieswas sent to 51 chief executives or chief ambulance officers, of whom 44 replied (86 per cent). Over 91 per cent felt there was a definite need for a recognized degree or diploma in paramedic studies and that the numbers of graduatesshould be regulated to allow career progression in 45 per cent. 88 per cent were of the opinion that there should be a state regulated paramedic qualification in the UK. 89 per cent stated that there should be a general paramediccouncil to overseeprofessionalaccountability. 89 per cent felt that a degree in paramedic studies should be a requisite for advancement to senior managementin the Ambulance Service. There were some fears as only 34 per cent were of the opinion that there should be a national qualifying examination as opposedto a local examination.
of the British
Trauma
Society
To date we have treated seven patients with fractures above total knee replacements using the Richards supracondylar femoral nail (Smith and Nephew Richards, Memphis, TN). This offers the advantages of reliable fracture fixation and minimum soft-tissue dissection. All the patients were women, mean age 69.5 years (39-85 years). Average time from total knee replacement to fracture was 3.3 years (3 days to 11 years). Mean time to union was 15.7 weeks (12-20 weeks) and mean follow up was 13.4 months (6-24 months). There were no significant post-operative complications and all but one patient achieved their previous level of mobility. The supracondylar femoral nail offers several advantages over other treatment modalities. The procedure can be performed through previous incisions,operative time is generally reduced and anatomical alignment is often more readily achieved. Extensive soft tissue dissection is unnecessaryso reducing the risks of non-union and infection. Furthermore, protected weight bearing can often be commencedearly. Whilst further evaluation is required, the supracondylar femoral nail may becomethe treatment ef choice for most fractures proximal to total knee replacements. J. Keenan, G. Chakrabarty and J.H. Newman (Bristol, UK) Treatmentof supracondylar femoral fracture above a fatal knee replacement by revision fo a custom made hinged prosthesis
Supracondylar fracture above a total knee arthroplasty (TKA) is a devastating complication for both patient and surgeon. Various methods of treatment are available including non-operative treatment, open reduction and internal fixation, external fixation, retrograde intramedullary nailing, intramedullary Rush pin fixation and revision arthroplasty. We have used a custom-made Endo-Model rotational knee prosthesis to treat seven casesof displaced supracondylar fracture above a total knee arthroplasty. The average age of the patients was 78 years and their average weight was 90 kg. The original prostheseshad been irt situ for between 4 weeks and 8 years. Two patients had primary internal fixation of the fracture which failed with a non-union at the fracture site, one patient had a tibia1 Steinman pin inserted for skeletal traction and four had immediate revision. All patients made a rapid post-operative recovery being mobile with the use of simple walking aids after 7 days and dischargedfrom hospital after an average of 3 weeks, The averagefollow-up period of these patients is 9 months. Unfortunately the patient who had a tibia1 Steinman pin inserted pre-operatively developed deep sepsisrequiring subsequentremoval of the prosthesis.At latest assessment four patients have had a good or excellent outcome as measured by the Bristol Knee Score. Two patients with recently inserted prostheseshave a fair result to date and continue to improve. Our experience demonstrates that the use of this custom-made implant to treat displaced supracondylar fractures above a TKA achieves good implant alignment, fixation and stability whilst allowing rapid recovery and mobilization. No long-term follow up is yet available but a quick return to pre-injury state is of particular benefit to elderly osteoporotic patients in whom these difficult fractures usually occur. The cost savingsof earlier mobilization and discharge serve to offset the high cost of the prosthesis.The technique should probably be reserved for
239
low fractures in which fixation is technically challenging or for failure of internal fixation. N. Cassidy, M. F&gibbon, C. Condron and R. Moran (Dublin, Ireland) Interleukind production in lower limb trauma
Interleukin-6 (IL-6) is a cytokine which is regarded as an early and integral mediator of the inflammatory response to trauma. Elevated systemic levels are demonstrated within hours of blunt injury and surgical procedures.This cytokine hasbeen implicated in the priming of neutrophils, the development of adult respiratory distress syndrome (ARDS) and multi-organ failure (MOF). Early and persistent high levels are associatedwith a poorer prognosis. Long-bone fractures, especiallyfemoral fractures are associated with an increased risk of systemic complications including ARDS and MOF. Little attention has been given to the contribution of lower-limb trauma which includes long-bone fractures to the systemicinflammatory load. We withdrew femoral artery and femoral vein blood samplesfrom 10 patients who came to theatre for surgical procedures on femoral or tibia1 shaft fractures. The serum was then analysed using an enzyme linked immunosorbent assayfor IL-6 levels. We found that the IL-6 level in the vein was usually twice the arterial level in each patient. There was no strong correlation with the Injury Severity Score or the time interval from injury to surgery. These preliminary results indicate that the injured limb with a long-bone fracture may be a significant source of IL-6. This study also shows that in measuring cytokine levels in trauma patients the site of blood sampling should be stated and consistentas there are significant differences in blood from different sites at identical times in these patients. M. Fitzgibbon, H.P. Redmond and R. Moran (Dublin, Ireland) The role of CD4+ T lymphocytes in elaborating cyfokine response in multiply injured patients
Few disorders can compete with sepsis as a major contributor to morbidity and mortality among seriously injured patients. A vast network of cytokines and other immunologicalfactors are fundamental to the mediation of sepsisand its sequelae.Trauma-relatedimmune responseis a mixed complex of events in which overstimulation and depressedfunction are coupled, leaving the injured patient susceptibleto serious infection. In a seriesof 100 injured patients with ISS> 21 we demonstrated that exaggerated releaseof polymorphonuclear neutrophils (PMNs) associated with significant lymphopenia occurs rapidly after severe injury and correlateswith poor outcome and sepsis development. The specificity of the immune responseis due to lymphocytes which makesthis significant lymphopenia an important event in the period post injury. The proposed division of cytokine-producing T lymphocytes into T helper 1 (Thl) and Th2 subsetswith profoundly different membrane proteins and functions, is currently a key issuein regulation of immune response.Theseproteins serve as phenotypic markers of lymphocyte subsets;CD4 is expressed predominantly on helper cells and CD8 on cytotoxic T cells. The exact mechanismwhich drives naive CD4’ T cells in either direction is unclear. Interleukin 12 (IL-12) a 70 kD heterodimer produced by activated monocytes and B cells,is believed to stimulate the differentiation of T helper cells to a predominantly Thl response.The ability of macrophagesand lymphocytes to stimulate each
240
Injury:
International
others’ functions provides an important amplification processfor specificimmunity, which may be lost following severeinjury. In a seriesof trauma patients (N = 6, ISS> Zl), we report the pattern of the Thl/Th2 cytokine model to be altered with decreasedplasma IFN-1/ and IL-2 on one hand, and elevated IL-10 on the other, measuredby specific immunoassaysand compared with age-matched normal controls. We also report significantly decreasedproduction of IL-12 after injury using a highly sensitive p70 specific monoclonal antibody sandwich ELISA immunoassay. This cytokine pattern represents an inert Thl responsein the post-traumatic phase, however this may be related to activation-induced cell death or apoptosisof CD4+ T cells, rather than a switch to Th2. We therefore investigated CD4/CD8ratios and lymphocyte apoptosis.Resultsdemonstrate alterations in CD4/CDS ratios following acute injury and particularly during septic episodes.Using flow cytometry PMN respiratory burst was found to be decreased and correlated well with clinical manifestationsof sepsis and was thus incorporated into the criteria for defining septic episodes.Low ratios of CD4+ T lymphocytes were associatedwith notable decreasein respiratory burst. Fas (CD95), a cell surface protein belonging to the tumour necrosisfactor (TNF) receptor family, is expressedpredominantly on activated T cells and hasbeen shown to bind to Fas ligand (FasL) resulting in target cell apoptosis. We therefore studied Fas-mediated lymphocyte apoptosis in acute severe injury and report preliminary results of increasedexpressionof CD95using flow cytometry. In conclusion, these results show the importance of the significant lymphopenia observed after injury and suggest that CD4+ Thl anergy in the post-traumatic phasemay be due to preferential activation of subpopulations of CD4’ helper T cellsby activated macrophages,OYto Fas-mediated CD4’ T lymphocyte apoptosis,or to impairment of monocyte-T cell interaction with decreased IL-12 resulting in production of distinct setsof cytokines which have discrete effector functions. M.E. Lovell, S. Sharma, S. Allcock and S.K. Hardy (Blackbum, UK) Insertion site for tibial nails, the continuing story
Recentwork has suggestedthat a patella splitting approach for insertion of intramedullary tibia1nailsis associatedwith an increasedincidence of anterior knee pain. We looked at 48 patients with tibia1fractures stabilized with intramedullary nails. Four nails were unreamed, the rest reamed. Thirty-five fractures were closed,eight Gustilo type I, three type II and two type III. Information about insertion approach and knee pain was available for 38 patients. Fifty per cent had anterior knee pain, 22 had a medial approach performed of whom 12 had pain, 16 had a patella tendon splitting approach of whom seven had pain (NS, x2= 0.43). Suitable X-rays were available to allow measurement of patella tendon shortening in 30 patients (patella included on X-ray view). This demonstrated patella tendon shortening of 2.8 per cent in the pain group (N = 14), 3.4 per cent in the no pain group (N = 16); 3.3 per cent in the split group (N = lo), 3.5 per cent in the medial approach group (N = 17, information on surgical approach not available for three patients). The range of shortening for all patients did not exceed 10 per cent. Literature suggeststhat patella tendon shortening can occur with excessive dissection required for a medial approach at this area of the knee. We
Journal
of the Care of the Injured
Vol. 28, No. 3,1997
agree with recent comments that a controlled trial is required to evaluate this problem further. D.F. McGeehan, F. Richardson, A. Newton and S. Bowers (Stafford, UK and Newport, UK) Training needs and preferences in the Ambulance Service of the United Kingdom
Paramedic training has improved greatly in the last 15 years largely due to the personal commitment of many doctors who have given freely of their time. In 1984, extended training for ambulancepersonnelwas introduced by the National Health Service Training Directorate (NHSTD) which has been at the forefront of teaching. In 1995most Ambulance Authorities achieved the target of a paramedicon every front-line ambulance.The commitment and training of paramedicsin the UK falls far behind those in other countries. In North America, paramedicstrain for over 3000h, becomeadept in advanced life support skills, drug administration and also work closely with Emergency departments. In South Africa, the critical care assistant obtains specialist registration with the South African Medical and Dental Council after the successfulcompletion of a 3 year course. Other countries, including Germany, Australia and Canada have considerably more financial investment in pre-hospital care. In the UK, paramedics are very keen to extend their training and expertise, freely giving up their time to attend courses. A questionnairewas sent to 210 paramedicsrequesting information on their interest in further training. There were 91 (46per cent) replies;96.77per cent were in favour of further training and 77.41per cent were of the opinion that further training should lead to professionalqualifications. That training provision should take the form of a regular daytime lecture/workshop was the preferred option in 66.6per cent. The training areaswhich were thought to be of high importance were Advanced Trauma Life Support (ATLS) (91.4 per cent), Advanced Cardiac Life Support (ACLS) (90.3 per cent) and Advanced Paediatric Life Support (APLS) (83.8per cent). Thosequestionedwere very keen to be taught practical proceduresincluding cricothyroidotomy (43 per cent), needle pleurocentesis (64.5 per cent) and interosseousaccess(47.3per cent). In responseto the question on trauma scoring,only 19.4 per cent thought it to be of high importance and 23.7 per cent thought it to be low in the list of teaching priorities. This is of vital importance to those who are consideringthe implementation of trauma systemsas it is vital to get the patient to the right place at the right time. A questionnaire on tertiary education for paramedic studieswas sent to 51 chief executives or chief ambulance officers, of whom 44 replied (86 per cent). Over 91 per cent felt there was a definite need for a recognized degree or diploma in paramedic studies and that the numbers of graduatesshould be regulated to allow career progression in 45 per cent. 88 per cent were of the opinion that there should be a state regulated paramedic qualification in the UK. 89 per cent stated that there should be a general paramediccouncil to overseeprofessionalaccountability. 89 per cent felt that a degree in paramedic studies should be a requisite for advancement to senior managementin the Ambulance Service. There were some fears as only 34 per cent were of the opinion that there should be a national qualifying examination as opposedto a local examination.