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Thesis (M.D.)--University of Adelaide, Dept. of Medicine, 1973.

Thesis (M.S.) -- University of Adelaide, Department of Surgery, 1980.

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published_or_final_version / Electrical and Electronic Engineering / Doctoral / Doctor of Philosophy

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Background: The D-Dimer test has a high negative predictive value used primarily to exclude clinically suspected possible thrombo-embolic disease. In Emergency Unit (EU) practice, this test is often done not only for suspected Pulmonary Emboli (PE) but also to rule out atypical PE. In South Africa, diagnostic usefulness of this test has not been evaluated in a private hospital EU. The health profile of patients presenting in public and private EUs is different and therefore, it was hypothesized that the usefulness of the DDimer test in these two settings may be different. Results of this study may inform private hospital EU best practice in the optimal utilization of this test. Objective: To evaluate the usefulness of the D-Dimer test in the diagnosis of PE at the Morningside MediClinic (MMC) private hospital EU in Johannesburg, South Africa. Patients and Methods: After approval by the University of the Witwatersrand Human Research Ethics Committee, audit of clinical records was done at the MMC EU from 1 March to 1 June 2009. Informed consent was not required from study subjects as the study was done retrospectively with data extracted from clinical records in an anonymous and delinked fashion. The study population included all patients who had a D-Dimer test done in the MMC EU as part of their diagnostic workup. Extracted data included demographic information, diagnoses and confirmatory tests done. Continuous and categorical variables of data collected were summarized using Stastistica version 9.0 statistical package. A Wells Score was calculated according to the Wells Criteria. Results: In the study period, 189 of 2948 (5%) patients seen at MMC EU had D-Dimers measured. Their population mean age was 57 years (range 38 – 84 years) and 51% were males. Positive D-Dimers were present in 40 (21%) of the total patient population sample group (189 patients). Within the diagnostic categories, the following percentages were the results found per category of the positive D-Dimers within each category: PE (5)(100%), Chest Infection (5)(56%), AMI (2)(33%), Arrhythmia (2)(33%), Hypertension (2)(25%), Chest Pain (6)(14%), Anxiety (3)(23%), Headache (1)(14%), Syncope (1)(14%) and Others (13)(32%). The mean Wells Score in PE was 3.6 (3.0-4.5.) indicating medium probability of PE. All other diagnostic groups had low probability Wells Scores. It was impossible to comment on findings in public hospitals, as there is no known literature found to date on an audit performed concerning the usefulness of the D-Dimer test in a public hospital or any of the public sector, in Johannesburg or elsewhere in South Africa, regarding the diagnosis of PE. However, data has been published by other countries regarding the D-Dimer in various hospital and EU settings (public and private). Conclusion: In the cohort, the D-Dimer was done in only a fifth of patients seen at the private MMC EU and it was positive in less than half of cases. The test yield was highest in PE and had high negative predictive value in more than half of non-PE diagnoses. Therefore, the results suggested that a positive D-Dimer is highly predictive of a diagnosis of PE in this private EU. A negative D-Dimer result appears to be largely associated with any of the non PE wide differential of diagnoses.

The studies documented here have demonstrated that similar to joint arthroplasty, VP causes FE with cardiovascular changes. Following the augmentation of each VB there is a transient acute response affecting the homeostasis of the cardiovascular system. This response is biphasic. Phase 1 was seen within 3 s after the beginning of bone cement injection and is likely to be due to a autonomous nerve reflex. Phase 2 was observed within ~16 s, reaching a peak response after ~30 s returning to a steady state between I and 5 minutes (approximately 10 % below pre-injection baseline). Consequently multiple VP caused baseline cardiovascular variables to progressively deteriorate. This fundamental response occurred whether bone cement or bone wax was used. A vent-hole did not prevent the peak response but attenuated the progressive deterioration of the baseline. Pathomechanism of Fat Embolism: The exact mechanism(s) responsible for the cardiovascular responses to FE are still not entirely clear. However several theories have been put forward in the literature (see Chapter 1). The present studies have eluciated the role of some of these variables. The primary mechanism responsible for FE has been attributed to an increase in IMP (Breed, 1974; Engesaeter et al., 1984; Orsini et al., 1987, Hofmann et al., 1999). The present investigation measured the IMP during VP and found that the peak increase in IMP (>500mmHg) was similar to that reported for arthroplasty. The consequences of an increase in IMP are 1) a release of bone marrow content into the venous system and 2) a likely stimulation of nerve endings within the bone marrow cavity. By using transoesophageal echocardiography, this thesis provides evidence that the emboli originate from the bone marrow cavity and not from the agglutination of plasma fat. Because the cardiovascular response was seen in the first seconds after the pressurisation (phase 1) and before the bone marrow content had reached the lung, it is most likely that this reaction was triggered by a nerve reflex. On the basis of either an up regulation of the vagus or a down regulation of the sympathetic tone. Pressurisation with bone cement and bone wax caused similar cardiovascular deterioration, which clearly gives evidence that bone cement monomer is not the only factor in this process. In the vent-hole group there was also a similar phase 1. Although the IMP was not measured in this group it is likely that the peak IMP was less in the vent hole group but still exceeding the threshold for nerve reflex stimulation. After the initial cardiovascular response (fall in HR and MABP) a secondary cardiovascular response occurred (phase 2). Two possible mechanisms responsible for phase 2 are: 1) the effect of the released bone marrow content and its mediators on the pulmonary and systemic vascular system and 2) continuous stimulation of nerve endings within the VB caused by the pressure of the injected material. Phase 2 was characterised by an increase in PAP and CVP and a decrease in MABP starting ~16 seconds after the beginning of the bone cement / bone wax injection. The time and response pattern for phase 2 was similar for each augmentation (VP1-VP2) and similar between the groups. This similarity gives evidence that the peak responses were a result of a reflex vasoconstriction of the lung vessels to the microembolisation of bone marrow particles (Byrick et al., 1989; Woo et al., 1995). Other authors also have reported that an increase in PVR was observed during FE (Wheelwright et al., 1993; Byrick et al., 1994), but this work is the first to suggest that a pulmonary vasoconstriction reflex may be involved. This is the first study which measured the cardiovascular responses during FE continuously, unlike other studies which measured responses after 3 to 5 minutes (Wheelwright et al., 1993; Byrick et al., 1994). In the vent-hole group, Q was also measured during the transient response and therefore it was possible to calculate the PVR. The results showed that PVR was increased 3 to 5 times the pre-injection value at the peak response proving evidence that an increase in PVR is likely to be responsible for the increase in PAP and CVP and the decrease in MBP Based on the observation that the wax and non-vent hole groups had similar peak responses to the vent hole group for PAP, CVP and MBP it can be concluded that PVR responses are also similar for all the groups. The bone cement and the bone wax group had similar peak responses, therefore bone cement monomer can not solely be responsible for the vasoconstriction of the lung vessels. Although the amount of the fat was likely to be reduced by using a vent-hole the peak responses were similar. This suggests that even a reduced amount of bone marrow content released in the vent-hole group exceeded the 'threshold' for initiating a reflex response. The fact that a certain threshold has to be reached to initiate a reflex response may explain why only a small percentage of patients develop FE during arthroplasty. Small amounts of bone marrow may not trigger the reflex. This finding is of significant clinical relevance as far as VP is concerned. To prevent the initiation of the reflex during injection of bone cement for VP or implantation of a prosthesis has to be performed as slowly as possible to reduce the amount of bone marrow content released into the circulation which reduces the risk of triggering reflex pulmonary vasoconstriction. The problem with medium viscosity bone cement used in this study is that it cures too rapidly. Therefore it is essential to find a bone cement material which can be injected much slower to reduce the amount of bone marrow content released and, consequently, the chance of triggering a nerve reflex. These findings are also relevant for joint arthroplasty. By reducing the injection pressure less bone marrow content is released into the circulation and the chances of initiating this reflex mechanism are minimised. Future studies are required to measure the cardiovascular changes by injecting bone cement at low speed. Because such bone cement is not yet available, it would be possible to use calcium phosphate cements instead. A similar amount of fat would be released but whether the magnitude of the cardiovascular effect is altered would be interesting to explore. The recovery of PVR was responsible for the recovery of MABP. This was quicker in the bone wax group compared to the group where bone cement was used. It is therefore likely that the bone cement monomer has a vasoconstrictor effect on the vascular system of the lung. Alternatively bone cement has been implicated in the increase of circulation levels of coagulating substances such as thrombin or fibrinopeptides (Dahl et al., 1988; Sharrock et al., 1995). However we could not demonstrate that bone cement monomer altered the peak reflex response. Several authors have implicated bone cement monomer as having an effect on the cardiovascular system (Berman et al., 1974). This is the first study which provides compelling evidence that bone cement plays a role during FE. The peak response for HR was different in the bone wax group compared to the cement groups. With bone wax HR decreased during phase 2 whereas with bone cement HR gradually increased. From the previous study we know that the fall in MABP and HR in phase 1 is caused by a nerve reflex (Chapter 3). This would normally result in an increase in sympathetic activity. In the bone cement group the primary peripheral vasoconstriction response was attenuated resulting in a secondary increase in HR in order to restore MABP. This dulled response may be attributed to the bone cement monomer. However in the bone wax group the sympathetic response caused a severe and rapid vasoconstriction to restore MABP. Therefore an increase in HR did not happen and HR dropped further in phase 2. This result may have a major impact on the clinical use of bone cement in the future, especially when treating patients with cardiovascular risk factors. Baseline Changes: The injection of five consecutive VB in the same animal caused a progressive decrease in MABP in all groups. The fall in MABP was primarily correlated to SVR. The fall in SVR is mostly likely caused either by: 1) vasoactive substances, or 2) a decrease in sympathetic tone. A vent hole was able to attenuate the progressive decrease in MABP. Because the quantity of bone marrow content released into the circulation was lower in the vent-hole group, compared to the bone cement group, the amount of vasoactive substances would also be lower in this group. This suggests that vasoactive substances are responsible for the decrease in SVR. The quantity of injected PMMA was not different between the vent hole and bone cement group. Therefore, the methylmethacrylate monomer does not seem to play a major role in the development of the fall in baseline MABP during multiple VP. The fact that the decrease in MABP was similar in the bone cement and bone wax group supports this theory as well, since a similar amount of bone marrow is released. Blood Gas Changes: In the present study, multiple VP induced prolonged hypoxaemia, hypercapnia and acidosis. According to the literature, the likely cause for these changes in arterial blood gases is ventilation-perfusion (V/Q) mismatch and pulmonary shunting, which is a consequence of the fat and marrow particles causing microembolisation of the pulmonary vessels (Modig et al., 1974; Pitto et al., 1998). The V/Q mismatching may also be accentuated by mediators causing pulmonary vasoconstriction (Woo et al., 1995). The severity of V/Q mismatch is likely to be correlated to the amount of bone marrow reaching the lung which was similar in the bone wax and bone cement group. A vent hole reduced the amount of fat released and therefore the mismatch. Consequently, PaCO2 and pHa did not significantly change and the fall in PaO2 in the vent hole group was less than the bone cement group. Similarly, Pitto et al. (1999) reported that the hypoxaemia that normally develops during hip arthroplasty, can be prevented if a vent hole is drilled into the distal femur and a vacuum applied. Clinical Implications: Surgeons have to be aware that FE occurs during VP and is similar to what happens during arthroplasty. Therefore VP can potentially cause hypotension, cardiac arrest and even death (personal communication with Prof. Jens R. Chapman). The potential risk increases with the number of augmented VBs. As a result of the current work it has been shown that a maximum of 3 - 4 VBs can be augmented safely in one operation and that cardiovascular monitoring is mandatory. A vent hole is also recommended to attenuate the adverse cardiovascular response. The use of bone substitute material does not reduce or prevent the risk of FE and consequently similar precautions are recommended.

224 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, Dept. of Medicine, 1973

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