Five-year results of a randomised controlled trial comparing cemented and cementless Oxford unicompartmental knee replacement using radiostereometric analysis.

BACKGROUND: Cementless fixation is an alternative to cemented unicompartmental knee replacement (UKR). The aim of this study was to determine if cementless UKR fixation is as good as cemented by comparing the five-year migration measured radiostereometric analysis (RSA) in a randomised controlled trial. METHODS: Thirty-nine patients were randomised to receive either a cemented or a cementless Oxford UKR and were studied at intervals up to five years to assess migration with RSA and radiolucencies with radiographs. RESULTS: During the first year there was a small and significant amount of migration, predominantly in an anterior direction, of both the cemented (0.24 mm, SD 0.32, p = 0.01) and cementless (0.26 mm, SD 0.31, p = 0.00) femoral components. Thereafter there was no significant migration in any direction. At no stage was there any significant difference between the migrations of the cemented or cementless femoral components. During the first year, particularly the first three months, the cementless tibial components subsided 0.28 mm (SD 0.19, p = 0.00). This was significantly (p = 0.00) greater than the subsidence of the cemented tibial component (0.09, SD 0.19, p = 0.28). Between the second and fifth years there was no significant migration of either cemented or cementless tibial components. At five years radiolucent lines occurred significantly less with cementless (one partial) compared to cemented (six partial and one complete) tibial components. CONCLUSIONS: As, between two and five years, there was no significant migration of cemented or cementless components, and no significant difference between them, we conclude that cementless fixation is as reliable as cemented. It may be better as there are fewer radiolucent lines.

The role of intra-operative cell salvage in patient blood management for revision hip arthroplasty: a prospective cohort study.

Cell salvage is an important component of blood management in patients undergoing revision hip arthroplasty surgery. However concerns regarding efficacy and patient selection remain. The aims of this study were to describe intra-operative blood loss, cell salvage re-infusion volumes and red blood cell transfusion rates for revision hip procedures and to identify factors associated with the ability to salvage sufficient blood intra-operatively to permit processing and re-infusion. Data were collected from a prospective cohort of 664 consecutive patients undergoing revision hip surgery at a single tertiary centre from 31 March 2015 to 1 April 2018. Indications for revision surgery were aseptic (n = 393 (59%)) fracture (n = 160 (24%)) and infection (n = 111 (17%)). Salvaged blood was processed and re-infused when blood loss exceeded 500 ml. Mean (SD) intra-operative blood loss was 1038 (778) ml across all procedures. Salvaged blood was re-infused in 505 of 664 (76%) patients. Mean (SD) re-infusion volume was 253 (169) ml. In total, 246 of 664 (37%) patients received an allogeneic red blood cell transfusion within 72 h of surgery. Patients undergoing femoral component revision only (OR (95%CI) 0.41 (0.23-0.73)) or acetabular component revision only (0.53 (0.32-0.87)) were less likely to generate sufficient blood salvage volume for re-infusion compared with revision of both components. Compared with aseptic indications, patients undergoing revision surgery for infection (1.87 (1.04-3.36)) or fracture (4.43 (2.30-8.55)) were more likely to generate sufficient blood salvage volume for re-infusion. Our data suggest that cell salvage is efficacious in this population. Cases where the indication is infection or fracture and where both femoral and acetabular components are to be revised should be prioritised.

Functional outcome of debridement, antibiotics and implant retention in periprosthetic joint infection involving the hip: a case-control study.

AIMS: Advocates of debridement, antibiotics and implant retention (DAIR) in hip periprosthetic joint infection (PJI) argue that a procedure not disturbing a sound prosthesis-bone interface is likely to lead to better survival and functional outcome compared with revision. This case-control study aims were to compare outcome of DAIRs for infected primary total hip arthroplasty (THA) with outcomes following primary THA and two-stage revision of infected primary THAs. PATIENTS AND METHODS: We retrospectively reviewed all DAIRs, performed for confirmed infected primary hip arthropasty (n = 82) at out institution, between 1997 and 2013. Data recorded included full patient information and type of surgery. Outcome measures included complications, mortality, implant survivorship and functional outcome. Outcome was compared with two control groups matched for gender and age; a cohort of primary THAs (n = 120) and a cohort of two-stage revisions for infection (n = 66). RESULTS: Mean age at DAIR was 69 years (33 to 87) and mean follow-up was eight years (2 to 17; standard deviation (sd) 5). A total of 52 (63%) of DAIRs were for early PJI (less than six weeks). Greater success in the eradication of infection with DAIR was identified with early PJI, comprising an interval less than a week between onset of symptoms and exchange of modular components with the DAIR procedure. Eradication of infection, complications and re-operation rates were similar in the DAIR and two-stage revision groups. For hips with successful eradication of infection with DAIR, the five-year survival (98%; 95% confidence interval (CI) 94 to 100) was similar to the primary THA group (98%; 95% CI 95 to 100) (n = 43; p = 0.3). The DAIR group had inferior mean Oxford Hip Scores (OHS) (38; 12 to 48) compared with the primary THA group (42; 15 to 48) (p = 0.02) but a significantly better mean OHS compared with the two-stage revision group (31; 0 to 48) (p = 0.008). Patients who required only one DAIR for eradication of infection had a similar mean OHS (41; 20 to 48) to the primary THA group (p = 0.2). CONCLUSION: The DAIR procedure is associated with a similar complication rate and ability to eradicate infection as two-stage revision. This study emphasises the need for exchange of modular components for improved chances of eradication of infection. This is the first study showing that DAIR is better than a two-stage revision regarding functional outcome. Cite this article: Bone Joint J 2017;99-B:614-22.

Hemiarthroplasty using cemented or uncemented stems of proven design: a comparative study.

National Institute of Clinical Excellence guidelines state that cemented stems with an Orthopaedic Data Evaluation Panel (ODEP) rating of > 3B should be used for hemiarthroplasty when treating an intracapsular fracture of the femoral neck. These recommendations are based on studies in which most, if not all stems, did not hold such a rating. This case-control study compared the outcome of hemiarthroplasty using a cemented (Exeter) or uncemented (Corail) femoral stem. These are the two prostheses most commonly used in hip arthroplasty in the UK. Data were obtained from two centres; most patients had undergone hemiarthroplasty using a cemented Exeter stem (n = 292/412). Patients were matched for all factors that have been shown to influence mortality after an intracapsular fracture of the neck of the femur. Outcome measures included: complications, re-operations and mortality rates at two, seven, 30 and 365 days post-operatively. Comparable outcomes for the two stems were seen. There were more intra-operative complications in the uncemented group (13% vs 0%), but the cemented group had a greater mortality in the early post-operative period (n = 6). There was no overall difference in the rate of re-operation (5%) or death (365 days: 26%) between the two groups at any time post-operatively. This study therefore supports the use of both cemented and uncemented stems of proven design, with an ODEP rating of 10A, in patients with an intracapsular fracture of the neck of the femur.

Cemented versus cementless Oxford unicompartmental knee arthroplasty using radiostereometric analysis: a randomised controlled trial.

The most common reasons for revision of unicompartmental knee arthroplasty (UKA) are loosening and pain. Cementless components may reduce the revision rate. The aim of this study was to compare the fixation and clinical outcome of cementless and cemented Oxford UKAs. A total of 43 patients were randomised to receive either a cemented or a cementless Oxford UKA and were followed for two years with radiostereometric analysis (RSA), radiographs aligned with the bone-implant interfaces and clinical scores. The femoral components migrated significantly during the first year (mean 0.2 mm) but not during the second. There was no significant difference in the extent of migration between cemented and cementless femoral components in either the first or the second year. In the first year the cementless tibial components subsided significantly more than the cemented components (mean 0.28 mm (sd 0.17) vs. 0.09 mm (sd 0.19 mm)). In the second year, although there was a small amount of subsidence (mean 0.05 mm) there was no significant difference (p = 0.92) between cemented and cementless tibial components. There were no femoral radiolucencies. Tibial radiolucencies were narrow (< 1 mm) and were significantly (p = 0.02) less common with cementless (6 of 21) than cemented (13 of 21) components at two years. There were no complete radiolucencies with cementless components, whereas five of 21 (24%) cemented components had complete radiolucencies. The clinical scores at two years were not significantly different (p = 0.20). As second-year migration is predictive of subsequent loosening, and as radiolucency is suggestive of reduced implant-bone contact, these data suggest that fixation of the cementless components is at least as good as, if not better than, that of cemented devices.

A semi-automated measurement technique for the assessment of radiolucency.

The assessment of radiolucency around an implant is qualitative, poorly defined and has low agreement between clinicians. Accurate and repeatable assessment of radiolucency is essential to prevent misdiagnosis, minimize cases of unnecessary revision, and to correctly monitor and treat patients at risk of loosening and implant failure. The purpose of this study was to examine whether a semi-automated imaging algorithm could improve repeatability and enable quantitative assessment of radiolucency. Six surgeons assessed 38 radiographs of knees after unicompartmental knee arthroplasty for radiolucency, and results were compared with assessments made by the semi-automated program. Large variation was found between the surgeon results, with total agreement in only 9.4% of zones and a kappa value of 0.602; whereas the automated program had total agreement in 81.6% of zones and a kappa value of 0.802. The software had a 'fair to excellent' prediction of the presence or the absence of radiolucency, where the area under the curve of the receiver operating characteristic curves was 0.82 on average. The software predicted radiolucency equally well for cemented and cementless implants (p = 0.996). The identification of radiolucency using an automated method is feasible and these results indicate that it could aid the definition and quantification of radiolucency.

The mid-term outcomes of the Oxford Domed Lateral unicompartmental knee replacement.

Mobile-bearing unicompartmental knee replacements (UKRs) with a flat tibial plateau have not performed well in the lateral compartment, owing to a high dislocation rate. This led to the development of the Domed Lateral Oxford UKR (Domed OUKR) with a biconcave bearing. The aim of this study was to assess the survival and clinical outcomes of the Domed OUKR in a large patient cohort in the medium term. We prospectively evaluated 265 consecutive knees with isolated disease of the lateral compartment and a mean age at surgery of 64 years (32 to 90). At a mean follow-up of four years (sd 2.2, (0.5 to 8.3)) the mean Oxford knee score was 40 out of 48 (sd 7.4). A total of 12 knees (4.5%) [corrected] had re-operations, of which four (1.5%) were for dislocation. All dislocations occurred in the first two years. Two (0.8%) were secondary to significant trauma that resulted in ruptured ligaments, and two (0.8%) were spontaneous. In four patients (1.5%) the UKR was converted to a primary TKR. Survival at eight years, with failure defined as any revision, was 92.1% (95% confidence interval 81.3 to 100). The Domed Lateral OUKR gives good clinical outcomes, low re-operation and revision rates and a low dislocation rate in patients with isolated lateral compartmental disease, in the hands of the designer surgeons.

An analysis of dislocation of the domed Oxford Lateral Unicompartmental Knee Replacement.

BACKGROUND: The Oxford Unicompartmental Knee Replacement (OUKR) uses a mobile bearing to minimise wear. Bearing dislocation is a problem in the lateral compartment as the ligaments are loose in flexion. A domed tibial component has been introduced to minimise the risk of dislocation, yet they still occur, particularly medially. The aim of this mechanical study was to compare the domed and flat tibial components and to identify surgical factors that influence the risk of dislocation. METHOD: A jig was constructed to assess the amount of vertical distraction of the lateral OUKR for a dislocation to occur. Three methods of dislocation were assessed: laterally, medially, 'over the wall' and anteriorly. The study focused on medial dislocation. RESULTS: Significantly (p=0.02) greater vertical distraction was required to dislocate the bearing with the domed tibia rather than the flat. For medial dislocation bearing distance from the wall, femoral component external rotation and tibial rotation were associated with significantly less distraction for dislocation. With the optimal technique with the domed tibia the distraction required to dislocate the bearing medially was 6.4 mm, whereas with poor technique it was 4.6 mm. CONCLUSIONS: This study suggests that to minimise the risk of dislocation the domed tibia should be used. The component should be implanted so the bearing is close to the wall, but does not hit it, and in flexion the femoral and tibial components should be neutrally aligned.

Corail uncemented hemiarthroplasty with a Cathcart head for intracapsular hip fractures.

The National Institute for Health and Clinical Excellence (NICE) guidelines from 2011 recommend the use of cemented hemi-arthroplasty for appropriate patients with an intracapsular hip fracture. In our institution all patients who were admitted with an intracapsular hip fracture and were suitable for a hemi-arthroplasty between April 2010 and July 2012 received an uncemented prosthesis according to our established departmental routine practice. A retrospective analysis of outcome was performed to establish whether the continued use of an uncemented stem was justified. Patient, surgical and outcome data were collected on the National Hip Fracture database. A total of 306 patients received a Cathcart modular head on a Corail uncemented stem as a hemi-arthroplasty. The mean age of the patients was 83.3 years (SD 7.56; 46.6 to 94) and 216 (70.6%) were women. The mortality rate at 30 days was 5.8%. A total of 46.5% of patients returned to their own home by 30 days, which increased to 73.2% by 120 days. The implant used as a hemi-arthroplasty for intracapsular hip fracture provided satisfactory results, with a good rate of return to pre-injury place of residence and an acceptable mortality rate. Surgery should be performed by those who are familiar with the design of the stem and understand what is required for successful implantation.

Improved fixation in cementless unicompartmental knee replacement: five-year results of a randomized controlled trial.

BACKGROUND: When used for appropriate indications, unicompartmental knee replacement is associated with fewer complications, faster recovery, and better function than total knee replacement. However, joint registries demonstrate a higher revision rate for unicompartmental knee replacement. Currently, most unicompartmental knee replacements are cemented; common reasons for revision include aseptic loosening and pain. These problems could potentially be addressed by using cementless implants, with coatings designed to improve fixation. The objectives of this study were to compare the quality of fixation as well as clinical outcomes of cemented and cementless unicompartmental knee replacements at five years of follow-up. METHODS: A randomized controlled trial was established with sixty-three knees (sixty-two patients) receiving either cemented (thirty-two patients) or cementless Oxford unicompartmental knee replacements (thirty patients). Fixation was assessed with fluoroscopic radiographs aligned to the bone-implant interface at one and five years. Outcome scores, including the Oxford Knee Score, Knee Society objective and functional scores, and Tegner Activity Score, were collected preoperatively and at six months and one, two, and five years postoperatively. At each postoperative time point, these were recorded as absolute scores and change from the preoperative score. RESULTS: Four patients died during the study period. There were no revisions. Mean operative time was nine minutes shorter in the cementless group (p = 0.049). At five years, there was no significant difference in any outcome measure except the Knee Society functional score and the change in the Knee Society functional score, which were significantly better in the cementless group (p = 0.003 for both). There were significantly more tibial radiolucencies in the cemented group (twenty of thirty knees versus two of twenty-seven knees; p < 0.001). There were nine complete radiolucencies in the cemented group and none in the cementless group (p = 0.01). CONCLUSIONS: Cementless fixation provides improved fixation at five years compared with cemented fixation in mobile-bearing unicompartmental knee replacements, maintaining equivalent or superior clinical outcomes with a shorter operative time and no increase in complications. LEVEL OF EVIDENCE: Therapeutic level I. See Instructions for authors for a complete description of levels of evidence.

Histology of the bone-cement interface in retrieved Oxford unicompartmental knee replacements.

INTRODUCTION: Radiolucent lines (RLL) are commonly seen at the cement-bone interface of knee replacements, yet are poorly understood. Although thin RLL are not associated with implant loosening or poor patient outcome there is still concern that they indicate sub-optimal fixation. The primary study aim is to characterise the histology at the cement-tibia interface in Oxford unicompartmental knee replacement (UKR). The second aim is to assess whether a correlation exists between the presence of a RLL and the type of tissue that predominates at the interface. METHODS: The radiology and histology of retrieved specimens of the interface from around firmly fixed tibial trays in ten patients undergoing revision between 1 and 19 years after Oxford UKR were studied. RESULTS: Pre-revision radiographs showed the presence of both full and partial RLL. On contact radiographs of 5mm thick sections of the interface the total percentage of radiolucency ranged from 0 to 90% between patients. There was no consistent pattern for the distribution of radiolucency. Histological assessment demonstrated that under every tibial component there were areas where there was direct contact and interdigitation between bone and cement. The amount of direct bone-cement contact was between 19% and 95% of the tibial tray surface area. The remaining tissue was mainly fibrocartilage but there was also fibrous tissue. The presence of radiolucency was strongly inversely correlated with the percentage of cement-bone contact. CONCLUSION: This study demonstrates that even with partial or complete RLL seen on radiographs there is still cement-bone contact, thus indicating that there is stable fixation.

Load transfer in the proximal tibia following implantation with a unicompartmental knee replacement: a static snapshot.

Unicompartmental knee replacement (UKR) is an appealing alternative to total knee replacement when the patient has isolated medial compartment osteoarthritis. A common observation post-operatively is radiolucency between the tibial tray wall and the bone. In addition, some patients complain of persistent pain over the proximal tibia antero-medially; this may be related to elevated bone strains in the tibia. Currently, there is no intentionally made mechanical bond between the vertical wall of an Oxford UKR and the adjacent bone; whether one exists or not will influence the load transmission in the proximal tibia and may affect the elevated tibia strain. The aim of this study was to investigate how introducing a mechanical tie between the tibial tray wall and the adjacent bone might alter the load carried into the tibia for both cemented and cementless UKRs. Strain energy density in the region of bone adjacent to the tray wall was considerably increased when a mechanical tie was introduced; this has the potential of reducing the likelihood of a radiolucency occurring in that region. Moreover, a mechanical tie had the effect of reducing proximal tibia strain, which may decrease the incidence of pain following implantation with a UKR.

Polyethylene wear of mobile-bearing unicompartmental knee replacement at 20 years.

The Oxford unicompartmental knee replacement (UKR) was designed to minimise wear utilising a fully-congruent, mobile, polyethylene bearing. Wear of polyethylene is a significant cause of revision surgery in UKR in the first decade, and the incidence increases in the second decade. Our study used model-based radiostereometric analysis to measure the combined wear of the upper and lower bearing surfaces in 13 medial-compartment Oxford UKRs at a mean of 20.9 years (17.2 to 25.9) post-operatively. The mean linear penetration of the polyethylene bearing was 1.04 mm (0.307 to 2.15), with a mean annual wear rate of 0.045 mm/year (0.016 to 0.099). The annual wear rate of the phase-2 bearings (mean 0.022 mm/year) was significantly less (p = 0.01) than that of phase-1 bearings (mean 0.07 mm/year). The linear wear rate of the Oxford UKR remains very low into the third decade. We believe that phase-2 bearings had lower wear rates than phase-1 implants because of the improved bearing design and surgical technique which decreased the incidence of impingement. We conclude that the design of the Oxford UKR gives low rates of wear in the long term.

The migration patterns of two versions of the Furlong cementless femoral stem: a randomised, controlled trial using radiostereometric analysis.

We have evaluated the difference in the migration patterns over two years of two cementless stems in a randomised, controlled trial using radiostereophotogrammetric analysis (RSA). The implants studied were the Furlong HAC stem, which has good long-term results and the Furlong Active stem, which is a modified version of the former designed to minimise stress concentrations between the implant and bone, and thus to improve fixation. A total of 23 Furlong HAC and 20 Furlong Active stems were implanted in 43 patients. RSA examinations were carried out immediately post-operatively and at six, 12 and 24 months post-operatively. The subsidence during the first year in the Furlong HAC stem, was approximately one-third that of the Furlong Active stem, the measured mean subsidence of the femoral head at six months being 0.27 mm (95% confidence interval (CI) 0.03 to 0.51) and 0.99 mm (95% CI 0.38 to 1.60), respectively (p = 0.03). One Active stem continued to subside during the second year. All hips, regardless of the type of stem were clinically successful as judged by the Oxford hip score and a derived pain score without any distinction between the two types of stem. The initial stability of the Furlong Active stem was not as good as the established stem which might compromise osseo-integration to the detriment of long-term success. The changes in the geometry of the stem, to minimise stress have affected the attainment of initial stability.

Polyethylene wear in Oxford unicompartmental knee replacement: a retrieval study of 47 bearings.

The Oxford Unicompartmental Knee replacement (UKR) was introduced as a design to reduce polyethylene wear. There has been one previous retrieval study involving this implant, which reported very low rates of wear in some specimens but abnormal patterns of wear in others. There has been no further investigation of these abnormal patterns. The bearings were retrieved from 47 patients who had received a medial Oxford UKR for anteromedial osteoarthritis of the knee. None had been studied previously. The mean time to revision was 8.4 years (sd 4.1), with 20 having been implanted for over ten years. The macroscopic pattern of polyethylene wear and the linear penetration were recorded for each bearing. The mean rate of linear penetration was 0.07 mm/year. The patterns of wear fell into three categories, each with a different rate of linear penetration; 1) no abnormal macroscopic wear and a normal articular surface, n = 16 (linear penetration rate = 0.01 mm/year); 2) abnormal macroscopic wear and normal articular surfaces with extra-articular impingement, n = 16 (linear penetration rate = 0.05 mm/year); 3) abnormal macroscopic wear and abnormal articular surfaces with intra-articular impingement +/- signs of non-congruous articulation, n = 15 (linear penetration rate = 0.12 mm/year). The differences in linear penetration rate were statistically significant (p < 0.001). These results show that very low rates of polyethylene wear are possible if the device functions normally. However, if the bearing displays suboptimal function (extra-articular, intra-articular impingement or incongruous articulation) the rates of wear increase significantly.

The implications of damage to the lateral femoral condyle on medial unicompartmental knee replacement.

With medial unicompartmental osteoarthritis (OA) there is occasionally a full-thickness ulcer of the cartilage on the medial side of the lateral femoral condyle. It is not clear whether this should be considered a contraindication to unicompartmental knee replacement (UKR). The aim of this study was to determine why these ulcers occur, and whether they compromise the outcome of UKR. Case studies of knees with medial OA suggest that cartilage lesions on the medial side of the lateral condyle are caused by impingement on the lateral tibial spine as a result of the varus deformity and tibial subluxation. Following UKR the varus and the subluxation are corrected, so that impingement is prevented and the damaged part of the lateral femoral condyle is not transmitting load. An illustrative case report is presented. Out of 769 knees with OA of the medial compartment treated with the Oxford UKR, 59 (7.7%) had partial-thickness cartilage loss and 20 (2.6%) had a full-thickness cartilage deficit on the medial side of the lateral condyle. The mean Oxford Knee Score (OKS) at the last follow-up at a mean of four years was 41.9 (13 to 48) in those with partial-thickness cartilage loss and 41.0 (20 to 48) in those with full-thickness loss. In those with normal or superficially damaged cartilage the mean was 39.5 (5 to 48) and 39.7 (8 to 48), respectively. There were no statistically significant differences between the pre-operative OKS, the final review OKS or of change in the score in the various groups. We conclude that in medial compartment OA, damage to the medial side of the lateral femoral condyle is caused by impingement on the tibial spine and should not be considered a contraindication to an Oxford UKR, even if there is extensive full-thickness ulceration of the cartilage.

Development of a model-based Roentgen stereophotogrammetric analysis system to measure polyethylene wear in unicompartmental arthroplasty.

One of the most important causes of failure in unicompartmental knee replacement (UKR) is polyethylene wear. The aim of this study was to develop and assess a novel Roentgen stereophotogrammetric analysis (RSA)-based method for the measurement of linear wear suitable for UKR. Model-based RSA was used to estimate the linear wear of polyethylene bearings in UKR. A phantom was used to validate the method using in vitro measured bearing thicknesses and the linear wear of ten control bearings was estimated in vivo. Computer aided design (CAD) models for the UKRs were used in the model-based RSA system. There was no statistically significant difference between the estimated and measured bearing thicknesses using the CAD models (p = 0.386). The precision of the linear wear measurement, expressed as the standard deviation of the difference between the estimated and measured bearing thickness was 0.163 mm. The bias (mean difference) was 0.030 mm. The use of RSA to measure in vivo wear in a UKR has been shown to be accurate in a phantom, and has been verified with in vivo measured controls. The technique does not require surgical implantation of marker balls and can be used retrospectively.

Drotrecogin alfa (activated) in severe falciparum malaria.

Drotrecogin alfa (activated) is a drug licensed for the treatment of severe sepsis. We describe the care of a 61-year-old man who developed multi-organ failure secondary to severe falciparum malaria infection with parasitaemia levels of 40%. Included in his care were an exchange blood transfusion and an infusion of Drotrecogin alfa (activated). Within hours of starting the infusion of Drotrecogin alfa (activated), the patient's clinical condition stopped deteriorating. Steady improvement followed with weaning from ventilatory assistance on day 14 post admission. The patient made a full recovery and was discharged home following rehabilitation. The indications for Drotrecogin alfa (activated) and the appropriateness of its use in severe malaria with multi-organ failure are discussed. Drotrecogin alfa (activated) may be a useful treatment in patients with multi-organ failure resulting from severe malaria.