SWINE FLU 1 GIUDANCE WORD (Oseltamivir, amantadine (review) and zanamivir for the prophylaxis of influenza Includes a review of NICE technology appraisal guidance 67)

Selasa, 29 September 2009

1 Guidance
This guidance has been prepared with the expectation that vaccination against influenza is undertaken in accordance with national guidelines. Vaccination has been established as the first-line intervention to prevent influenza and its complications, and the use of drugs as recommended in this guidance should not detract from efforts to ensure that all eligible people receive vaccination.
This guidance does not cover the circumstances of a pandemic, an impending pandemic, or a widespread epidemic of a new strain of influenza to which there is little or no community resistance.
1.1 Oseltamivir and zanamivir are recommended, within their marketing authorisations, for the post-exposure prophylaxis of influenza if all of the following circumstances apply.
• National surveillance schemes have indicated that influenza virus is circulating .
• The person is in an at-risk group as defined in section 1.3.
• The person has been exposed (as defined in section 1.4) to an influenza-like illness and is able to begin prophylaxis within the timescale specified in the marketing authorisations of the individual drugs (within 36 hours of contact with an index case

for zanamivir and within 48 hours of contact with an index case for oseltamivir).
• The person has not been effectively protected by vaccination (as defined in section 1.5).
1.2 The choice of either oseltamivir or zanamivir in the circumstances described in section 1.1 should be determined by the healthcare professional in consultation with patients and carers. The decision should take into account preferences regarding the delivery of the drug and potential adverse effects and contraindications. If all other considerations are equal, the drug with the lower acquisition cost should be used.
1.3 For the purpose of this guidance, people at risk are defined as those who fall into one or more of the clinical risk groups defined, and updated, each year by the Chief Medical Officer. The current list includes people with:
• chronic respiratory disease (including asthma that requires continuous or repeated use of inhaled or systemic steroids or with previous exacerbations requiring hospital admission)
• chronic heart disease
• chronic renal disease
• chronic liver disease
• chronic neurological disease
• immunosuppression
• diabetes mellitus.
People who are aged 65 years or older are also defined as at-risk for the purpose of this guidance.
1.4 Exposure to an influenza-like illness is defined as close contact with a person in the same household or residential setting who has had recent symptoms of influenza.
1.5 People who are not effectively protected by vaccination include:
• those who have not been vaccinated since the previous influenza season
• those for whom vaccination is contraindicated, or in whom it has yet to take effect
• those who have been vaccinated with a vaccine that is not well matched (according to information from the Health Protection Agency) to the circulating strain of influenza virus.
1.6 During localised outbreaks of influenza-like illness (outside the periods when national surveillance indicates that influenza virus is circulating generally in the community), oseltamivir and zanamivir may be used for post-exposure prophylaxis in at-risk people living in long-term residential or nursing homes, whether or not they are vaccinated. However, this should be done only if there is a high level of certainty that the causative agent in a localised outbreak is influenza, usually based on virological evidence of infection with influenza in the index case or cases.
1.7 Oseltamivir and zanamivir are not recommended for seasonal prophylaxis of influenza.
1.8 Amantadine is not recommended for the prophylaxis of influenza.
2 Clinical need and practice
2.1 Influenza is an acute infection of the respiratory tract caused by the influenza A and B viruses. The symptoms of influenza are fever accompanied by respiratory symptoms such as sneezing, coughing, runny nose and sore throat and systemic symptoms such as malaise, myalgia, chills and headaches. Gastrointestinal symptoms such as nausea, vomiting and diarrhoea are also common. Influenza infection is usually self-limiting and lasts for
3–4 days, with some symptoms persisting for 1–2 weeks. The severity of the illness can vary from asymptomatic infection to
life threatening complications. The most common complications are secondary bacterial infections such as otitis media, pneumonia and bronchitis.
2.2 Influenza occurs in a seasonal pattern with epidemics in the winter months, typically between December and March. The illness is highly contagious and is spread from person to person by droplets of respiratory secretions produced by sneezing and coughing. Influenza is commonly transmitted through household contacts, with the highest attack rates in children. People who live in residential accommodation and those who work in healthcare settings are at a higher risk of infection. The influenza attack rate is the probability that a person develops influenza over the influenza season. It is expressed as the proportion of people exposed to risk who develop the disease during the period under consideration. The influenza attack rate depends on the circulating level of influenza. It is estimated that yearly influenza epidemics in the UK cause between 12,000 and 13,800 deaths.
2.3 Influenza-like illness, which can be caused by a variety of infectious agents, is a clinical diagnosis made on the basis of symptoms. The causative agent for an influenza-like illness cannot be determined clinically and diagnosis requires laboratory testing. Influenza activity is monitored through surveillance schemes, which record the number of new GP consultations for influenza-like illness per week per 100,000 population. In England, normal seasonal activity is currently defined as 30–200 consultations, with greater than 200 defined as an epidemic. In Wales, the corresponding figures are 25–100, and greater than 400. In addition, there are virological monitoring schemes based on the isolation of the virus from clinical specimens. ‘Normal seasonal activity’, as measured by these surveillance schemes, corresponds to the term ‘circulating’ in ‘Guidance on the use of oseltamivir and amantadine for the prophylaxis of influenza’ (NICE technology appraisal guidance 67).
Accurate monitoring of influenza activity requires analysis of clinical, virological and epidemiological information.
2.4 The management of influenza is supportive and consists of relieving symptoms while awaiting recovery. For people in at-risk groups who can start therapy within 48 hours of the onset of an influenza-like illness, treatment with the antiviral drugs oseltamivir or zanamivir is recommended in line with ‘Guidance on the use of zanamivir, oseltamivir and amantadine for the treatment of influenza’ (NICE technology appraisal guidance 58). Complications require specific management, and antibiotics are used for secondary bacterial infections.
2.5 Vaccination has been established as the first-line intervention to prevent influenza and its complications. In the UK, the Department of Health currently recommends that people who are at risk of influenza infection or complications are vaccinated at the beginning of each winter. Such people are those with chronic respiratory, cardiovascular, renal, liver or neurological disease, people with diabetes, people who are immunosuppressed, people aged 65 and older, people who work or live in residential care facilities, carers of at-risk people, healthcare and other essential workers and poultry workers.
2.6 Antiviral drugs are also used for the prevention of influenza. They may be given to people who have been in contact with a person with influenza-like illness (post-exposure prophylaxis) and may be given in the absence of known contact when it is known that influenza is circulating in the community (seasonal prophylaxis). If seasonal prophylaxis is given, it is carried out for longer periods to cover the duration of the influenza season. Seasonal prophylaxis may be considered in exceptional situations such as an antigenic mismatch between circulating strains of the influenza virus and that used for vaccination which would mean that at-risk people are not effectively protected by vaccination. Prophylaxis may also be used to control outbreaks of influenza within a residential community.
3 The technologies
Oseltamivir
3.1 Oseltamivir (Tamiflu, Roche) is a neuraminidase inhibitor that is active against influenza A and B viruses. It prevents viral release from infected cells and subsequent infection of adjacent cells. It has a marketing authorisation for post-exposure prophylaxis in people 1 year of age or older following contact with a clinically diagnosed influenza case when influenza virus is circulating in the community. The appropriate use of oseltamivir for prevention of influenza should be determined on a case-by-case basis by the circumstances and the population requiring protection. In exceptional situations (for example in the case of a mismatch between the circulating and vaccine virus strains, and a pandemic situation) seasonal prevention can be considered in people 1 year of age or older. For post-exposure prophylaxis, oseltamivir should be started within 48 hours of contact with an index case of influenza-like illness and continued for 10 days. For seasonal prophylaxis, oseltamivir is given for up to 6 weeks. Oseltamivir is administered orally.
3.2 Adverse effects associated with oseltamivir include gastrointestinal symptoms, bronchitis and cough, dizziness and fatigue and neurological symptoms such as headache, insomnia and vertigo. Skin rashes and allergic reactions and, rarely, hepatobiliary system disorders have been reported. Convulsions and psychiatric events, mainly in children and adolescents, have also been reported but a causal link has not been established. For full details of adverse effects and contraindications, see the summary of product characteristics (SPC).
3.3 Oseltamivir costs £16.36 for a 10-day course for an adult (excluding VAT; ’British national formulary’ [BNF] edition 54). Costs may vary in different settings because of negotiated procurement discounts.
Amantadine
3.4 Amantadine (Lysovir, Symmetrel, Alliance Pharmaceuticals) acts against influenza A virus by blocking viral replication. The marketing authorisation recommends amantadine prophylactically in people particularly at risk. This can include those with chronic respiratory disease or debilitating conditions, the elderly and those living in crowded conditions. It can also be used for members of families in which influenza has already been diagnosed, for control of institutional outbreaks or for those in essential services who are unvaccinated or when vaccination is unavailable or contraindicated. It is also recommended as post-exposure prophylaxis in conjunction with inactivated vaccine during an outbreak until protective antibodies develop, or in people who are not expected to have a substantial antibody response (because of immunosuppression). Amantadine is licensed for use in people aged 10 years or older. The SPC states that treatment is recommended for as long as protection from infection is required and that in most instances this is expected to be for 6 weeks. In clinical practice this corresponds to its use as seasonal prophylaxis. For post-exposure prophylaxis, amantadine is usually given for
4–5 days. Amantadine is administered orally.
3.5 The adverse effects associated with amantadine are often mild and transient. The most commonly reported effects are gastrointestinal disturbances such as anorexia and nausea, and central nervous system effects such as loss of concentration, dizziness, agitation, nervousness, depression, insomnia, fatigue, weakness and myalgia. Central nervous system effects are most common in older people. For full details of adverse effects and contraindications, see the SPC.
3.6 Amantadine costs £2.40 for five capsules (100 mg each), £4.80 for 14 capsules and £5.55 for 150 ml syrup (50 mg/5 ml) (excluding VAT; BNF edition 54). Costs may vary in different settings because of negotiated procurement discounts.
Zanamivir
3.7 Zanamivir (Relenza, GlaxoSmithKline) is a neuraminidase inhibitor that is active against influenza A and B viruses. It prevents viral release from infected cells and subsequent infection of adjacent cells. It has a marketing authorisation for post-exposure prophylaxis of influenza A and B in adults and children (5 years and older) following contact with a clinically diagnosed case in a household. In exceptional circumstances, zanamivir may be considered for seasonal prophylaxis of influenza A and B (for example, during a community outbreak in the case of a mismatch between circulating and vaccine strains, and in a pandemic situation). For post-exposure prophylaxis zanamivir should be initiated within 36 hours of contact with an index case of influenza-like illness and continued for 10 days. For seasonal prophylaxis, zanamivir is given for up to 28 days. Zanamivir is administered by oral inhalation using an inhaler device.
3.8 Adverse effects associated with zanamivir are rare. They include bronchospasm and allergic phenomena. For full details of adverse effects and contraindications, see the SPC.
3.9 The price of zanamivir was reduced during the course of the appraisal to £16.36 for a 10-day course. The price of zanamivir currently listed in the BNF is £24.55 for a 10-day course (excluding VAT; BNF edition 54). Costs may vary in different settings because of negotiated procurement discounts.
4 Evidence and interpretation
The Appraisal Committee (appendix A) considered evidence from a number of sources (appendix B).
4.1 Clinical effectiveness
4.1.1 The Assessment Group carried out a systematic search for randomised controlled trials (RCTs) conducted in people in contact with clinically diagnosed influenza or people for whom seasonal prophylaxis would be appropriate. The population was divided into children, adults and older people, with each group being further subdivided into healthy or at risk of developing complications of influenza. The three drugs could be used for seasonal or post-exposure prophylaxis, with outbreak control referring to post-exposure prophylaxis in settings where people live or work in close proximity (for example, in residential care). Twenty-two RCTs were identified by the systematic review and a further RCT was provided in a sponsor’s submission. No head-to-head RCTs were identified. The background circulating levels of influenza for the duration of the individual RCTs were often not reported clearly.
4.1.2 In most RCTs, the effectiveness of antiviral drugs was measured as cases of influenza prevented. Cases of influenza were defined as either symptomatic laboratory-confirmed influenza or clinical illness. The efficacy outcome was presented as the relative risk and protective (or prophylactic or preventive) efficacy of developing influenza with and without prophylaxis. The relative risk is the ratio of the proportion of people developing influenza in the treatment group to the proportion developing influenza in the control group. The lower the relative risk the higher the efficacy of prophylaxis. The protective efficacy is the percentage of people for whom prophylaxis could prevent infection. It is calculated by subtracting the relative risk from 1 (and is expressed as a percentage).
4.1.3 Evidence was submitted by consultees that the incidence of influenza-like illness has been falling consistently over the last 10 years. This has resulted in the lowering of the threshold levels of the surveillance schemes. In addition, it was stated that the influenza season as defined by the surveillance schemes does not correspond exactly to the period during which the virus is circulating in the community as indicated by virological monitoring and virus isolation from clinical specimens. Lastly, it was apparent that outbreaks of influenza occur within localised areas, especially in residential care settings, outside of the influenza season.
Oseltamivir
4.1.4 Two RCTs of oseltamivir for seasonal prophylaxis, both included in the previous appraisal (TA67), were in healthy adults and one was in older people within a residential care setting. A meta-analysis of the two seasonal prophylaxis trials in adults (n = 1039) gave a relative risk of developing symptomatic laboratory-confirmed influenza of 0.27 (95% confidence interval [CI] 0.09 to 0.83). The study (n = 548) of seasonal prophylaxis in older people showed a 92% protective efficacy for symptomatic laboratory-confirmed influenza (p = 0.002), with an 86% relative reduction in secondary complications.
4.1.5 Two studies, one of which was not included in the original appraisal, were of post-exposure prophylaxis in households with mixed populations of adults and children. These two RCTs (n = 1747) showed a protective efficacy against symptomatic laboratory-confirmed influenza of 89% (p < 0.001) in one study and 73% in the other. When the results of the two RCTs were pooled by meta-analysis, the resulting relative risk was 0.19 (95% CI 0.08 to 0.45) and the protective efficacy was therefore 81%. Analysis of data limited to children aged 1–12 years from another trial of post exposure prophylaxis showed a protective efficacy of 64% (relative risk 0.36). 4.1.6 The Assessment Group stated that oseltamivir was of equivalent efficacy in vaccinated and unvaccinated people. No evidence of reduced sensitivity was observed in trials but surveillance data suggest viral resistance to oseltamivir is emerging. Amantadine 4.1.7 No new RCTs of amantadine additional to those considered in the previous appraisal (TA67) were identified. Of three trials of seasonal prophylaxis two trials were in unvaccinated healthy adults and one trial in older people in residential care who were inadequately vaccinated. In one study in healthy adults (n = 318), the relative risk for clinical symptoms with amantadine prophylaxis was 0.4 (95% CI 0.08 to 2.03). Another study (n = 285) in healthy military personnel found no difference in the incidence of acute respiratory illness. The studies of the efficacy of seasonal prophylaxis were limited by low attack rates. For the trial in older people in residential care no results were reported as there was no evidence of an influenza epidemic in this group during the trial. 4.1.8 Two trials investigated outbreak control, one in healthy mostly vaccinated adolescents and one in healthy unvaccinated adults. The study (n = 536) of outbreak control in vaccinated adolescent males in a boarding school reported a relative risk of 0.17 (95% CI 0.08 to 0.37) for clinical influenza and a protective efficacy of 90% (95% CI 0.66 to 0.97) for symptomatic laboratory-confirmed influenza. This study also demonstrated that the protective effect of amantadine prophylaxis was limited to the period of prophylaxis. The second study (n = 10,053) of outbreak control in unvaccinated adults in semi-isolated engineering schools reported a relative risk for clinical influenza of 0.59 (95% CI 0.49 to 0.70) with amantadine prophylaxis and showed some evidence that prophylaxis reduced the severity and duration of influenza illness. 4.1.9 The Assessment Group could not draw firm conclusions about the impact of vaccination status on the efficacy of amantadine prophylaxis. No information was available from the RCTs on the degree of viral resistance. However, virological monitoring has documented resistance to amantadine and it is reported that 37% of viral isolates are resistant to amantadine. Development of resistance can occur relatively rapidly during treatment and can lead to the failure of prophylaxis. Zanamivir 4.1.10 Four new trials not included in the previous appraisal (TA67) were identified by the Assessment Group: one of seasonal prophylaxis in at-risk adolescents and adults, one of post-exposure prophylaxis in a mixed population, and two of outbreak control in at-risk older people in residential care. A further new RCT, of seasonal prophylaxis in healthcare workers, formed part of the sponsor submission. A trial (n = 1107) of zanamivir as seasonal prophylaxis in healthy adults showed a protective efficacy of 68% (95% CI 37 to 83) against symptomatic laboratory-confirmed influenza. The trial was conducted in an influenza season where the vaccine and circulating strain were mismatched. In the unvaccinated subgroup, the protective efficacy was 60% (95% CI 24 to 80). A second study (n = 319) of zanamivir for seasonal prophylaxis in healthcare workers showed no statistically significant difference in the development of symptomatic laboratory-confirmed influenza. There was also a study (n = 3363) of zanamivir for seasonal prophylaxis in community-dwelling at-risk adolescents and adults (aged 12 years and above). For the intent-to-treat population the protective efficacy against symptomatic laboratory-confirmed influenza was 83% and the relative risk was 0.17 (95% CI 0.07 to 0.44). The relative risk did not vary according to vaccination status. The relative risk for developing confirmed influenza with complications was 0.12 (95% CI 0.02 to 0.73). The subgroup of people aged 65 and above, some of whom had further risk factors for influenza complications, showed a relative risk of 0.20 (95% CI 0.02 to 1.72). 4.1.11 A trial (n = 1291) of zanamivir given for 10 days for post-exposure prophylaxis to all household contacts (aged 5 years or older) of a person with an influenza-like illness showed a relative risk for symptomatic laboratory-confirmed influenza of 0.18 (95% CI 0.08 to 0.39). Another trial (n = 837) of 10-day zanamivir for post-exposure prophylaxis in household contacts showed a protective efficacy of 79% (95% CI 62 to 89, relative risk 0.21). Fewer households in the treatment group had contacts who developed complications of laboratory-confirmed influenza (p = 0.01). Two trials (reported jointly; n = 288) investigated the use of zanamivir for 5 days for post-exposure prophylaxis in household contacts. The relative risk for developing symptomatic laboratory-confirmed influenza was 0.33 during prophylaxis, and the length of illness was shorter in the treatment group (p = 0.016). 4.1.12 Two studies (n = 519) investigated the prevention of influenza outbreaks in older people in long-term residential care. The available data from one of these trials are limited. The second trial was conducted in mostly unvaccinated people and prophylaxis conferred a protective efficacy for symptomatic laboratory-confirmed influenza of 32% during influenza A outbreaks (95% CI 27 to 67). 4.1.13 Some studies tested the susceptibility of viral isolates to zanamivir and found no evidence of viral resistance. 4.2 Cost effectiveness 4.2.1 The Assessment Group identified seven cost-effectiveness studies that included oseltamivir, amantadine or zanamivir for the prophylaxis of influenza, one of which was a sponsor submission from the manufacturer of oseltamivir. No cost-effectiveness analyses were submitted by the manufacturers of amantadine and zanamivir. Three cost-effectiveness studies were UK based and took an NHS perspective (including the assessment for the original appraisal, TA67). One study from the UK NHS perspective estimated that the cost effectiveness of oseltamivir for post exposure prophylaxis compared with no prophylaxis or treatment was approximately £30,000 per quality-adjusted life year (QALY) gained and compared with no prophylaxis followed by oseltamivir treatment was about £52,000 per QALY gained. The second UK study, the assessment undertaken for the original appraisal, included vaccination as a prophylactic strategy. The model related to seasonal prophylaxis only. All three drug strategies were dominated by vaccination as a prophylactic strategy. 4.2.2 The submission from the manufacturer of oseltamivir reported a model to estimate the cost effectiveness of oseltamivir for seasonal and post-exposure prophylaxis of influenza, comparing it with amantadine, zanamivir and no prophylaxis for adults and children older than 12 years who were healthy or at risk, and for children aged 1–12 years and 1–5 years. A cost-effectiveness analysis was undertaken for the comparison of oseltamivir with amantadine or usual care. For the comparison of oseltamivir with zanamivir, it was assumed that both drugs are equally effective and a cost minimisation analysis was undertaken. The Assessment Group reanalysed the results from the manufacturer’s model for oseltamivir to generate full incremental cost-effectiveness estimates (the manufacturer’s submission presented pair-wise comparisons rather than a full incremental analysis). Oseltamivir for post-exposure prophylaxis gave incremental cost-effectiveness ratios (ICERs) below £8000 per QALY gained for both groups of children, less than £2000 for at-risk adults and about £27,000 for healthy adults. For children in both age groups oseltamivir as seasonal prophylaxis gave ICERs above £46,000 per QALY gained. For healthy or at-risk adults and children (older than 12 years) oseltamivir was dominated by zanamivir (it was less effective and more costly), and for the at-risk group the ICERs for amantadine and zanamivir were less than £16,000 per QALY gained. The model was sensitive to the changes in assumptions for attack rates and the number of GP visits per household. 4.2.3 The Assessment Group conducted an independent economic assessment. The three drugs were compared with each other and with no prophylaxis for three age groups: ‘children’ (aged 1–14 years), ‘adults’ (aged 15–64 years) and ‘older people’ (older than 65 years). Each age group was subdivided into healthy and at risk, and each of these six subgroups was further divided on the basis of vaccination status. 4.2.4 The model assumed that prophylaxis would only be considered when it is known that influenza is circulating in the community above a threshold of 30 new GP consultations for influenza-like illness per week per 100,000 population. The duration of the influenza season was calculated as the period for which the number of new GP consultations for influenza-like illness per week was above the threshold level of 30 (previously 50) per 100,000 population for the past 20 influenza seasons (1987–8 to 2006–7).The mean duration of the influenza season was calculated to be 5.71 weeks. It was assumed that vaccination is effective over the whole of the season but that drugs are effective only during the period over which they are taken. Hence the preventive efficacy of antivirals was adjusted according to the proportion of the influenza season for which the drugs were taken. 4.2.5 The model did not consider the benefits of prophylaxis in preventing transmission of influenza from the person who receives prophylaxis to others who might otherwise have contracted the illness from this person. 4.2.6 The probability that a person exposed to the influenza virus develops influenza depends on the influenza attack rate, the prophylactic efficacy of the intervention strategy and the person’s vaccination status. For amantadine it also depends on the probability that influenza is of type A, and on the degree of resistance of the virus to the drug. The baseline influenza attack rate is the probability that a person develops influenza over the influenza season. The model assumed this differs in each age group and within the models for seasonal and post-exposure prophylaxis. For seasonal prophylaxis the probability was 0.174 in children, 0.062 in adults and 0.052 in older people. For post-exposure prophylaxis it was 0.189 in children, 0.088 in adults and 0.088 in older people. The probability that influenza-like illness was true influenza was derived from Royal College of General Practitioners’ data. This was estimated to be 0.5 across all groups. The probability that influenza was influenza A virus was based on virological surveillance data for 12 influenza seasons (1995–6 to 2006–7). The overall mean probability that a case of influenza was influenza A was estimated to be 0.72. 4.2.7 The protective efficacies of vaccination, amantadine, oseltamivir and zanamivir were derived from the review of clinical effectiveness (and Cochrane reviews for vaccination). The relative risks for vaccination were 0.36 for healthy children, 0.35 for healthy adults and 0.42 for older people. The protective efficacy of vaccination reduced the probability of developing influenza without prophylaxis in the model. The joint benefit of vaccination and prophylaxis was assumed to be cumulative – that is, the effectiveness of prophylaxis was applied only to the unvaccinated proportion of the population. 4.2.8 There was a lack of clinical-effectiveness evidence for a number of subgroups in the cost-effectiveness analysis. Because of this lack of evidence the relative risk for seasonal prophylaxis with amantadine was taken from a study of unvaccinated healthy adults and applied to all population subgroups. For post-exposure prophylaxis with amantadine, efficacy was taken from a single study of outbreak control in vaccinated healthy adolescents and applied to all groups in the model. The model also assumed, based on data from the 2006–7 season, that in 37% of influenza cases people were resistant to amantadine. For seasonal prophylaxis with oseltamivir the results of the study in healthy unvaccinated adults were applied to healthy and at-risk adults and children, and the results of the trial in at-risk people in residential care were applied to healthy and at-risk older people. For post-exposure prophylaxis with oseltamivir, a meta-analysis was performed of two trials from healthy adults. The results were applied to the healthy and at-risk adult and older subgroups, and the results of the subgroup analysis for children in these trials were applied to the healthy and at-risk child subgroups. For zanamivir seasonal prophylaxis, a trial in healthy and mostly unvaccinated adults was used to calculate the relative risk for the healthy adults and the child groups (both at risk and healthy). A study of seasonal prophylaxis in at-risk adults supplied estimates for the at-risk adult and the older populations. For post-exposure prophylaxis with zanamivir a meta-analysis of three trials in adults and children was conducted and the results applied to all population groups. 4.2.9 The model included the probability of adverse effects from vaccination and amantadine only. Adverse effects from oseltamivir and zanamivir were assumed to be mild and self-limiting and not to have an impact on a person’s health-related quality of life. 4.2.10 The model also included the probabilities of developing complications from influenza or influenza-like illness, of receiving antibiotics, of hospitalisation because of a complication (including intensive care treatment), and of death from a complication related to an influenza-like illness. 4.2.11 Estimates of health-related quality of life were obtained from oseltamivir studies. The method for obtaining utility values used in the model was non-reference case, derived from measures on a 10-point scale from the oseltamivir trials. The adverse effects of amantadine were assumed to cause a 0.2 utility decrement for a mean duration of 5 days. Health utility decrements associated with complications of influenza-like illness were derived from a study that used committee consensus to reach estimates and were assumed to operate for the duration of complications in clinical trials for oseltamivir. 4.2.12 The model included costs for acquisition and administration of vaccination and antiviral prophylaxis and treatment, costs associated with the management of adverse effects, consultation costs, and the costs of antibiotics and hospitalisation, including intensive care. In the base case, the model assumed that each prescription of prophylaxis required a separate GP consultation. 4.2.13 Sensitivity analyses were carried out using the new lower price for zanamivir which changed during the course of the appraisal. The effect of multiple prescriptions per GP consultation (for example, for family contacts) was explored. Seasonal prophylaxis would be considered in the exceptional event of a mismatch between circulating and vaccine virus strains. In such a situation the protective efficacy of vaccination would decrease, the extent of such a decrease being determined by the degree of mismatch. This was explored by analyses in which the relative risk for vaccination was 0.5 or 0.75. Because the trials for oseltamivir and zanamivir occurred in different settings with differing circulating levels of influenza, virus strains and populations, the differing estimates of efficacy are not strictly comparable. To explore the impact of this, an analysis was conducted in which both drugs were considered to be of equal efficacy. Further analyses exploring the effect of assuming resistance to oseltamivir and varying the influenza attack rates were also conducted. 4.2.14 The Assessment Group model gave the following results for seasonal prophylaxis. In healthy children, oseltamivir economically dominated amantadine and zanamivir. That is, treatment with oseltamivir was expected to cost less and result in more QALYs gained. For unvaccinated children the ICER was £44,007 per QALY gained and for vaccinated children it was £129,357 per QALY gained. For at-risk children oseltamivir dominated the other drugs, with an ICER of £16,630 per QALY gained for unvaccinated children and £51,069 per QALY gained for vaccinated children. In healthy adults oseltamivir dominated the other drugs, with ICERs of £147,505 per QALY gained in unvaccinated adults and £427,184 per QALY gained in vaccinated adults. For at-risk adults oseltamivir again dominated the other drugs, with ICERs of £63,552 per QALY gained in unvaccinated people and £186,651 per QALY gained in vaccinated people. For healthy older people oseltamivir dominated the other drugs, with ICERs of £49,742 per QALY gained in unvaccinated people and £121,728 per QALY gained in vaccinated people. In at-risk older people oseltamivir dominated the other drugs, with ICERs of £38,098 per QALY gained for unvaccinated people and £93,763 per QALY gained for vaccinated people. 4.2.15 For post-exposure prophylaxis in healthy children zanamivir economically dominated oseltamivir and amantadine, with ICERs of £23,225 per QALY gained in unvaccinated children and £71,648 per QALY gained in vaccinated children. For post-exposure prophylaxis in at-risk children zanamivir dominated the other drugs, with ICERs of £8233 for unvaccinated children and £27,684 for vaccinated children. For post-exposure prophylaxis in healthy adults oseltamivir dominated zanamivir and amantadine, with ICERs of £34,181 for unvaccinated adults and £103,706 for vaccinated adults. For post-exposure prophylaxis in at-risk adults oseltamivir dominated the other drugs, with ICERs of £13,459 per QALY gained for unvaccinated adults and £43,970 for vaccinated adults. In healthy older people oseltamivir dominated zanamivir and amantadine, with an ICER of £10,716 per QALY gained for unvaccinated people and £28,473 for vaccinated people. For post exposure prophylaxis in at-risk older people oseltamivir again dominated, with ICERs of £7866 for unvaccinated people and £21,608 for vaccinated people. 4.2.16 When the lower price of zanamivir was used in the economic model it had little impact on the outcome of the comparisons made in the base case for seasonal prophylaxis except for at-risk adults. In this group zanamivir was no longer dominated by oseltamivir; the ICER was £53,159 per QALY gained for zanamivir compared to no treatment. For post-exposure prophylaxis the price reduction led to improvements in the cost effectiveness of zanamivir for healthy and at-risk children. In general, the estimates for cost effectiveness were sensitive to the influenza attack rates, the level of viral resistance, vaccine efficacy, the threshold used to define when influenza is circulating in the community, the relative efficacy of oseltamivir and zanamivir and the risk of hospitalisation in people without complications. For seasonal prophylaxis, the estimates were sensitive to the discount rate and for post-exposure prophylaxis they were sensitive to the use of multiple prescriptions for prophylaxis per GP visit. 4.3 Consideration of the evidence 4.3.1 The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of oseltamivir, amantadine and zanamivir, having considered evidence on the nature of the condition and the value placed on the benefits of oseltamivir, amantadine and zanamivir by people with exposure to influenza like illness, those who represent them, and clinical specialists. It was also mindful of the need to take account of the effective use of NHS resources. 4.3.2 The Committee accepted that influenza causes a wide spectrum of respiratory illness of varying severity, and can lead to a number of potentially serious complications, especially in certain at-risk groups. The Committee discussed the definition of at-risk groups for whom prophylaxis might be particularly suitable and decided that they would be best defined in the same way as for the current recommendations for vaccination. From the outset the Committee was of the view that vaccination has appropriately been established as the first-line intervention to prevent influenza and its complications, and was mindful that the use of drug prophylaxis should not in any way detract from efforts to ensure that all eligible people are vaccinated at the beginning of each influenza season. However, the Committee also accepted that because of the antigenic variation in circulating influenza viruses, vaccination may not always be fully effective in a particular season and thus a mismatch between vaccine and circulating virus strains could result in vaccination conferring significantly lower protection than predicted. 4.3.3 Because prophylaxis is given after contact with a person with clinically defined influenza-like illness and not confirmed influenza, the Committee accepted that a crucial factor in determining the effectiveness and cost effectiveness of antiviral drugs would be the probability that a person with influenza-like illness has true influenza. The Committee agreed that this probability would be highest when the virus was known to be circulating in the community, and that a method of routinely identifying periods of circulation of influenza viruses was needed in order to determine when influenza prophylaxis should be recommended. Such a method would need to take account both of the probability that influenza-like illness was influenza and of the influenza attack rate because the cost effectiveness depended on the assumptions for both these parameters. 4.3.4 The Committee noted that the surveillance scheme used to determine levels of influenza activity in the community (as recommended by the Health Protection Agency) was based on clinical consultations but that influenza activity as defined by the threshold levels of these consultation rates did not always coincide with laboratory-based virological evidence. The Committee heard from clinical specialists that the threshold levels were an artificial construct that may not be suitable for defining when drug prophylaxis would be most efficacious because they were not created for this purpose. 4.3.5 The Committee was aware that virological testing was possible and that results could be available within 24–48 hours. However, the Committee recognised that routine testing in individual cases was impractical and that the delay caused by awaiting test results could affect the timing of the use of prophylaxis with respect to the exposure to infection and therefore alter its efficacy. The Committee accepted that there were other indicators of influenza activity, both single and in combination, but that the evidence for cost effectiveness placed before it was based on the surveillance scheme threshold levels. The Committee was also aware that outbreaks of influenza were common in localised environments (such as residential care establishments) outside the influenza season as defined by the thresholds, and that unless such outbreaks could also be identified, it would not be possible to establish situations in which the use of prophylaxis would be cost effective. 4.3.6 The Committee considered the evidence for effectiveness of the individual drugs and the emergence of additional evidence since the publication of TA67. The Committee accepted that the submitted evidence indicated that oseltamivir and zanamivir were clinically effective when used either as seasonal or as post exposure prophylaxis. However there was more limited evidence for the efficacy of amantadine prophylaxis in differing settings. It noted that there were no head-to-head trials of the interventions and that because the individual trials were conducted in differing populations, the results might not reflect accurately any differences in efficacy between the drugs. In addition, the Committee noted that the relative risks used in the economic modelling needed to be extrapolated from existing trials to the many groups for which there is no trial data. Therefore, the Committee noted that it would need to be cautious in appraising the results of the economic analysis for groups for which the suggestion of underlying differences in efficacy between the drugs was based on assumptions and not trial evidence. 4.3.7 The Committee accepted that the neuraminidase inhibitors were generally safe and well tolerated. It was aware of concerns that have been raised with regulatory authorities in Canada, Japan and the USA about possible neuropsychiatric events associated with oseltamivir in adolescents, but that no specific guidance regarding safety has been issued by the European Medicines Agency or the Medicines and Healthcare products Regulatory Agency. The Committee accepted that amantadine was associated with more frequent adverse effects. The Committee also accepted evidence of viral resistance to amantadine, and noted that there was also evidence of increasing resistance to the neuraminidase inhibitors although it was currently low. 4.3.8 The Committee considered the consequences of developing influenza and the costs and health outcomes of these assumed in the economic model. It was aware of clinical specialist opinion that there was no evidence that the use of prophylaxis decreased hospitalisations associated with influenza-like illness as included in the model. However, the Committee accepted that preventing an influenza infection could logically and plausibly be expected to result in a decrease in the adverse consequences of the illness. The Committee considered the multiple prescriptions by GPs to contacts of a case of influenza-like illness. It was aware that the use of multiple prescriptions could improve the cost effectiveness of prophylaxis. However the Committee was persuaded that prescribing without seeing the patient would not have a straightforward effect on cost effectiveness as additional GP time would be required to ensure safe prescribing and indirect usage may not result in satisfactory adherence. In addition, the Committee considered that this approach would not normally be thought of as good practice and would not be used routinely. 4.3.9 The Committee next considered the structure and general approach of the economic analyses. The Committee was aware that the models submitted by the manufacturer and the Assessment Group were not dynamic models. That is, the models did not account for effects of influenza prophylaxis in preventing general transmission of infection, the development of herd immunity, the potential for the development of drug resistance with wider use of prophylaxis and the effect of treatment of influenza-like illness on attack rates. The Committee appreciated that some aspects of this approach to modelling additional benefits could improve the cost effectiveness of the antiviral agents but on the other hand there were potential disbenefits that would make prophylaxis less cost effective. The Committee considered that any additional dynamic benefits of drug prophylaxis in a population with an effective vaccination programme in place would be limited. The Committee was also aware that dynamic models were technically complicated and that the current evidence available to them would not have been sufficient to support this modelling approach. The Committee concluded that the evidence available from the submitted models was an appropriate basis on which to make a decision and that on balance an alternative dynamic modelling approach would not change its overall conclusions. 4.3.10 The Committee considered the cost effectiveness of the use of seasonal prophylaxis. In doing so it was aware that clinical specialist opinion did not favour the use of drug prophylaxis in this manner. The Committee also noted that because seasonal prophylaxis would be considered only in exceptional situations such as a mismatch between vaccine and circulating virus, the efficacy of vaccination assumed should be intermediate between the extremes of the values used for unvaccinated and vaccinated relative risks in the model. The Committee concluded that the ICERs for the various subgroups examined in the modelling suggested that overall seasonal prophylaxis was not a cost-effective use of NHS resources. The Committee specifically noted that the Assessment Group-modelled ICER for seasonal prophylaxis in unvaccinated at-risk children was approximately £17,000 per QALY gained with a high probability of this being cost effective at a threshold of £20,000. However, this ICER was very sensitive to changes in the assumed attack rate and the Committee was aware that the values for attack rates used in the economic analysis, which were derived from intensively monitored clinical trials, were likely to be higher than those that would be expected to occur routinely in the general population. In addition, the relative risk of infection for this subgroup of children had been extrapolated from a trial in healthy adults and was not based on direct empirical evidence. Therefore the Committee agreed that it could not recommend seasonal prophylaxis with oseltamivir, amantadine or zanamivir. 4.3.11 The Committee considered the results of the economic evaluation for the use of the drugs for post-exposure prophylaxis. The Committee was aware that prophylaxis would not normally be considered in clinical practice for healthy people given the self limiting nature of influenza and the potential for adverse effects with medication. The Committee noted that the ICERs for the various subgroups indicated that the use of post-exposure prophylaxis was cost effective in at-risk groups only who had either not been vaccinated or not been effectively protected by vaccination. This would include people in whom vaccination was contraindicated or had yet to take effect and circumstances when the vaccine and circulating strains of virus were sufficiently different to mean that vaccination did not provide adequate protection. The ICERs in these subgroups ranged from £7866 per QALY gained for unvaccinated at-risk older people, to £8233 per QALY gained for unvaccinated at-risk children, to £13,459 per QALY gained for unvaccinated at-risk adults. The Committee also noted that the contact with the index case would need to be of a sufficiently intense degree, such as that experienced by living together in the same residential setting, normally the same household. The Committee concluded that post-exposure prophylaxis was a cost effective use of resources for at-risk persons who were not adequately protected by vaccination, but only when it has been established that influenza is circulating in the community. 4.3.12 The Committee then discussed which, if any, of the two neuraminidase inhibitors should be prescribed if post-exposure prophylaxis was considered appropriate in the subgroups identified. The Committee was aware of the limitations in the evidence base for comparative efficacy of the two drugs and it was not persuaded that there was evidence of differential effectiveness between the two drugs. However, the Committee noted that the drugs were administered differently and that zanamivir was not licensed for children under 5. The Committee concluded that it was not possible to give specific recommendations for one or other of the neuraminidase inhibitors, and therefore the decision as to which to prescribe should be determined by the healthcare professional in consultation with patients and carers on a case-by-case basis, taking into account preferences regarding the delivery of the drug and potential adverse effects and contraindications. If all other considerations are equal, the choice should be based on the less costly option within the marketing authorisations of the products. 4.3.13 The Committee carefully considered the need for managing outbreaks that occur outside the influenza season as defined by the surveillance threshold. It noted that such outbreaks often occurred in residential care establishments and were frequently associated with poor outcomes and complications in vulnerable populations. The Committee noted that the population in residential care was most likely to be older people or people otherwise at risk of influenza complications. It was mindful that, because the neuraminidase inhibitors are only effective against true influenza, the cost effectiveness of the use of prophylaxis in such situations would depend on the probability that the influenza-like illness was influenza. The Committee noted that this probability was low in the absence of wider circulation of influenza. Therefore, the Committee considered it important that in such situations there should be firmer evidence that the influenza-like illness was influenza. Such evidence could be supplied by virological testing. In addition, the Committee was aware that in the event of an influenza outbreak within a residential setting, the attack rates were likely to be substantially higher than those used in the base case in the model for post-exposure prophylaxis, and mortality in at-risk subgroups would be significant. In the residential care setting this would therefore result in better cost effectiveness of post-exposure prophylaxis than the model estimates. For the exceptional circumstances of at-risk people in residential care with a confirmed out-of-season outbreak of influenza the Committee accepted that post exposure prophylaxis with oseltamivir and zanamivir would be a cost effective use of NHS resources. The Committee considered other people who lived together in a residential setting, such as a prison or boarding school. It noted that such populations would comprise mostly healthy people for whom the consequences of influenza infection would be minor. The Committee agreed that such populations would not be exceptions and prophylaxis during outbreaks outside the influenza season would not be cost effective unless people in those populations were in an at-risk group. Therefore the Committee recommended that outside the periods when national surveillance indicates that influenza virus is circulating, oseltamivir and zanamivir may still used as options for post-exposure prophylaxis in vaccinated or unvaccinated people living in long-term residential or nursing homes, but only if there is a high level of certainty that a localised outbreak is occurring, usually based on virological evidence of infection with influenza in the incident case or cases. 4.3.14 The Committee noted that there was no new evidence for the efficacy of amantadine in various subgroups since the publication of TA67. In addition, a high incidence of viral resistance to amantadine has developed and, compared with the neuraminidase inhibitors, amantadine is associated with a greater incidence of adverse effects. The Committee noted that the economic analysis did not indicate that amantadine would be a cost-effective use of resources in any subgroup for any indication. Therefore the Committee did not recommend amantadine for prophylaxis of influenza. 5 Implementation 5.1 The Healthcare Commission assesses the performance of NHS organisations in meeting core and developmental standards set by the Department of Health in ‘Standards for better health’ issued in July 2004. The Secretary of State has directed that the NHS provides funding and resources for medicines and treatments that have been recommended by NICE technology appraisals normally within 3 months from the date that NICE publishes the guidance. Core standard C5 states that healthcare organisations should ensure they conform to NICE technology appraisals. 5.2 'Healthcare standards for Wales’ was issued by the Welsh Assembly Government in May 2005 and provides a framework both for self-assessment by healthcare organisations and for external review and investigation by Healthcare Inspectorate Wales. Standard 12a requires healthcare organisations to ensure that patients and service users are provided with effective treatment and care that conforms to NICE technology appraisal guidance. The Assembly Minister for Health and Social Services issued a Direction in October 2003 that requires local health boards and NHS trusts to make funding available to enable the implementation of NICE technology appraisal guidance, normally within 3 months. 5.3 NICE has developed tools to help organisations implement this guidance (listed below). These are available on our website (www.nice.org.uk/TA158). • Costing report and costing template to estimate the savings and costs associated with implementation. • Audit support for monitoring local practice.

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Pemeriksaan C-Reaktif Protein pada Sepsis

Sepsis merupakan keadaan yang serius tetapi jarang menular karena disebabkan oleh bakteri. Hal ini terjadi apabila bakteri (yang dapat berasal dari paru, usus, traktus urinarius) mengeluarkan toksin yang menyebabkan system imun tubuh melawan organ dan jaringan tubuh sendiri.(1)
Sepsis dapat menimbulkan kondisi yang menakutkan karena jika tidak teratasi dapat menimbulkan komplikasi yang serius yang dapat merusak ginjal, paru, otak dan pendengaran. Tetapi dengan mempelajari dan mengenali tanda-tanda sepsis maka kondisi buruk tersebut dapat teratasi dan anak dapat sembuh sempurna.(1)
Berbagai kelompok umur dapat mengalami sepsis, tetapi prevalensi tertinggi terserang sepsis adalah bayi dan anak-anak dimana system imunnya tidak cukup kuat untuk melawan infeksi yang sangat berat. Orang dewasa yang mengalami immuno compromise, sebagaimana kondisi pada penderita penyakit kronis dan HIV, juga lebih mudah mengalami sepsis.(1)
Mortalitas sepsis berat di negara sudah berkembang sudah menurun sampai hanya 9% akan tetapi di negara sedang berkembang seperti Indonesia masih sangat tinggi yaitu 50-70%, dan apabila sudah terjadi syok septik dan disfungsi organ multipel angka mortalitas 80%.(2)
Saat ini patogenesis sepsis dan syok septic sudah lebih dimengerti. Keseimbangan antara pro- dan anti-inflamasi dan mediator-mediator yang dilepaskan merupakan suatu jaring-jaring yang kompleks dan menyebabkan manifestasi klinis dengan derajat yang berbeda.(2)
Konsep terbaru penanganan sepsis berat, dan syok septik yaitu meliputi: early goal directed therapy dalam waktu 6 jam sejak ditegakkan diagnosis di rumah sakit dengan terapi cairan agresif, obat-obatan inotropik, dan vasopresor dapat menurunkan angka kematian. Sebaliknya resusitasi cairan yang terlambat, menyebabkan ekspresi gen inflamasi, aktivasi endotel, trombosis, dan disfungsi/gagal organ multiple.(2)
Tanda-tanda sepsis pada anak sulit dinilai sehingga peranan laboratorium sangat penting untuk menegakkan diagnosa sepsis. Salah satu pemeriksaan laboratorium yang digunakan sebagai pemeriksaan penunjang pada sepsis adalah serum CRP (C-Reactive Protein). Protein ini diproduksi oleh hepar apabila terjadi proses peradangan pada tubuh kita.(1,3,4)
Pemeriksaan CRP ini sangat umum digunakan untuk mendiagnosa dan memonitor aktivitas peradangan dan keadaan infeksi. Kadar CRP berkurang pada kondisi dengan terapi kortikosteroid atau terapi lain yang mendepresi sistem immune. CRP juga dapat digunakan untuk memonitor pada pemberian terapi kanker dan infeksi karena kadarnya dapat meningkat dan kembali normal dengan cepat.(1,4)
Berdasarkan penelitian yang dilakukan William (1998), pemeriksaan kadar CRP serial sangat berguna dalam evaluasi diagnostik pada bayi-bayi dengan dugaan infeksi.(5)

TINJAUAN PUSTAKA

Definisi

Sepsis adalah kumpulan gejala klinis dari kelainan yang disebabkan oleh karena adanya bakterimia.(6)
Sepsis merupakan keadaan gawat darurat yang sering ditemukan di ruang perawatan intensif anak. Penyulit yang sering adalah syok septic dan disfungsi organ multipel.(2)
CRP (C-Reaktif Protein)
Pemeriksaan CRP adalah pemeriksaan darah dengan cara melihat kadar CRP dalam darah. CRP merupakan petanda radang (inflammatory marker) dimana substansi ini akan muncul jika tubuh mengalami respon peradangan.(7,8,9)
Kadar CRP yang tinggi di dalam darah menunjukkan adanya proses peradangan pada tubuh tetapi tidak dapat diketahui penyebab dan lokasinya.(7,8,9)

Protein C-reaktif (CRP)
Protein C-reaktif (CRP) adalah suatu alfa-globulin yang diproduksi di hepar dan kadarnya akan meningkat dalam 6 jam di dalam serum bila terjadi proses inflamasi akut. Kadar CRP dalam plasma dapat meningkat dua kali lipat sekurang-kurangnya setiap 8 jam dan mencapai puncaknya setelah kira-kira 50 jam. Setelah pengobatan yang efektif dan rangsangan inflamasi hilang, maka kadar CRP akan turun secepatnya, kira-kira 5-7 jam waktu paruh plasma dari CRP eksogen(2,8)
Protein ini disebut demikian karena ia bereaksi dengan C-polisakaride yang terdapat pada pneumokokus. Semula disangka bahwa timbulnya protein ini merupakan respons spesifik terhadap infeksi pneumokokus, tetapi ternyata sekarang bahwa protein ini adalah suatu reaktan fase akut, yaitu indicator nonspesifik untuk inflamasi, sama halnya seperti LED. Tetapi berbeda dengan LED, kadar CRP tidak dipengaruhi oleh anemia, kehamilan atau hiperglobulinemia. Pada penderita dengan inflamasi yang berkaitan dengan kelainan imunologis, kadar CRP kembali normal bila pengobatan immunosupresif berhasil.(2,8)
Pemeriksaan CRP lebih sensitive dibandingkan dengan LED karena pada keadaan inflamasi kadar CRP lebih cepat meningkat yaitu dalam 6 jam dari awal terjadinya inflamasi. Sedangkan LED kadarnya meningkat setelah satu minggu dari awal terjadinya inflamasi. Kadar CRP dapat berbeda dari berbagai laboratorium tetapi menurut standar internasional kadar normal CRP adalah 0 – 1,0 mg/dL atau <10mg/L (SI unit).(4) Faktor yang mempengaruhi akurasi pemeriksaan CRP adalah: (4,8,9,10,11,12) 
1. Aktivitas / latihan yang berlebihan Aktivitas yang berlebihan dapat menimbulkan cedera jaringan. Selain itu latihan atau aktivitas yang berlebihan dapat meningatkan panas tubuh dimana kemungkinan terburuk adalah terjadinya heat stoke. Suhu tubuh yang tinggi cenderung menggandakan semua reaksi kimia intraselular, sehingga pada pemeriksaan CRP kadarnya meningkat.
2. Penggunaan terapi hormone, misalnya kontrasepsi oral Yaitu terapi untuk mencegah kehamilan dengan mengubah siklus reproduksi. Terapi ini biasanya memberikan hasil positif palsu pada pemeriksaan CRP. Reaksi ini akan dikenali sebagai reaksi inflamasi walaupun sebenarnya tidak terjadi proses peradangan.
3. Penggunaan IUD Pemasangan alat kontrasepsi dalam rahim biasanya akan menimbulkan reaksi peradangan karena masuknya benda asing dalam tubuh akan merangsang respon inflamasi., sehingga kadar CRP dalah darah maningkat
4. Hamil Reaksi hormonal yang terjadi pada wanita hamil akan dikenali sebagai reaksi inflamasi. Sehingga pada pemeriksaan CRP kadarnya akan meningkat. Range normal kadar CRP pada wanita hamil <20 mg/L
5. Obesitas Obesitas berhubungan dengan hipertensi dan penyakit jantung. Pemeriksaan CRP sangat sensitive terhadap penyakit jantung.
6. Penggunaan obat-obatan anti inflamasi non steroid (NSID), aspirin, atau kortikosteroid. Obat-obat anti inflamasi akan menekan respon peradangan.
7. Penggunaan Pravastin, obat-obat penurun kolesterol. Profil lemak dalam darah sangat berhubungan dengan risiko penyakit jantung koroner dan stroke dimana sangat berhubungan dengan reaksi peradangan. Penggunaan obat-obat penurun kolesterol menurunkan risiko penyakit jantung koroner dan stroke, sehingga kadar CRP dalam darah juga berkurang.
Cara Pemeriksaan CRP Sebelum dilakukan pemeriksaan CRP, pasien harus berpuasa selama 12 jam. Spesimen diambil dari darah vena ± 5 ml, dikumpulkan dalam botol tanpa anti koagulan. Selanjutnya segera dikirimkan ke Laboratorium Patologi Klinik atau laboratorium khusus immunology. Immunologi Sepsis Sepsis berkaitan dengan Sindroma Respon Radang Sistemik (SRRS). Sekarang diduga bahwa SRRS disebabkan oleh sepsis akibat dari cedera jaringan pasca respon hospes terhadap produk-produk bakteri misalnya endotoksin dari bakteri gram negative dan kompleks asam lipoteikoat-peptidoglikan dari bakteri gram positif. Manifestasi kardiopulmonal pada sepsis gram negative (H. influinzae, N. meningitides, E. coli, Pseudomonas) dapat ditiru dengan injeksi endotoksin atau faktor nekrosis tumor (FNT). Hambatan kerja FNT oleh antibody monoclonal anti-FNT sangat memperlemah manifestasi syok septic pada model percobaan. Bila komponen dinding sel bakteri dilepaskan ke dalam aliran darah, sitokin teraktivasi, dan selanjutnya dapat menyebabkan kekacauan fisiologis lebih lanjut. Jumlah sitokin yang terkait dengan SRRS terus bertambah dan sekarang mencakup factor nekrosis tumor (FNT), interleukin (IL)-1, -6, dan -8, factor pengaktif trombosit (platelet-activiting factor = PAF) dan interferon.(2,7)
Baik sendirian ataupun kombinasi, produk-produk bakteri dan sitokin proradang dalam kombinasi, produk-produk bakteri dan sitokin proradang memicu respon fisiologis untuk menghentikan penyerbu (invander) mikroba. Respon ini adalah :
(1) aktivasi system komplemen;
(2) aktivasi faktor Hageman (factor XII), yang kemudian mencetuskan tingkatan-tingkatan koagulasi;
(3) peepasan hormon adrenokortikotropin dan beta-endorfin,
(4) rangsangan neutrofil polimorfonuklear, dan
(5) rangsangan system kalikrein-kinin. FNT dan mediator radang lain meningkatkan permeabilitas vaskuler, menimbulkan kebocoran kapiler difus, mengurangi tonus vaskuler, dan terjadinya ketidakseimbangan antara perfusi dan kenaikan kebutuhan metabolic jaringan. Aktivitas mediator radang atau respon yang berlebihan berperan dalam patogenesis sepsis.(2,7,8)

Manifestasi Klinis 
Manifestasi Klinis yang menjadi dasar diagnostik pada sepsis adalah sebagai berikut: (1,6,9) 
1. Keadaan umum : menurun (not doing well), malas minum (poor feeding), hipo/hipertermia, edema, sklerema.
2. Sistem susunan saraf pusat : hipotonia, irritable, high pitch cry, kejang, letargi, tremor, fontanella cembung. 3. system saluran pernafasan : pernafasan tidak teratur, napas cepat (>60 x/menit), apnea, dispnea, sianosis.
4. system kardiovaskuler : takikardia (>160 x/menit), bradikardia (< 100 x/menit), akral dingin, syok.
5. Sistem saluran cerna : retensi lambung, hepatomegali, mencret, muntah, kembung.
6. system hematology : kuning, pucat, splenomegali, ptekie, purpura, perdarahan.
Adapun penggolongan sepsis berdasarkan manifestasi klinis adalah sebagai berikut: (6,9) 
1. early onset : terjadi 5 hari pertama pasca lahir, dengan gejala klinis yang timbulnya mendadak, serta gejala sistemik yang berat. Terutama mengenai system saluran nafas, sifatnya progresif dan akhirnya syok
2. late onset: timbul setelah umur 5 hari, sering disertai manifestasi klinis adanya gangguan system susunan saraf pusat
3. nosocomial infection : yaitu infeksi yang terjadi pada neonatus tanpa risiko infeksi, yang timbul lebih dari 48 jam saat dirawat di Rumah Sakit. Kriteria Diagnostik Kriteria diagnostik sepsis dikelompokkan sebagai berikut: (5,6,9)
1. Possible suspect sepsis : bila terdapat 3 gejala klinis dari 6 kelompok di atas
2. Probable sepsis : bila terdapat 3 gejala klinis dan adanya kelainan laboratories
3. Proven sepsis : bila terdapat 3 gejala klinis dan kultur darah positif Pemeriksaan Penunjang
Bila sindroma klinis mengarah ke sepsis, perlu dilakukan evaluasi sepsis secara menyeluruh. Hal ini termasuk biakan darah, pungsi lumbal, analisis dan kultur urin, serta foto dada.(1,6,9) Diagnosis sepsis ditegakkan dengan ditemukannya kuman pada biakan darah. Pada pemeriksaan darah tepi dapat ditemukan neutropenia dengan pergeseran ke kiri (imatur:total seri granulosit > 0,2). Selain itu dapat dijumpai pula trombositopenia. Adanya peningkatan reaktans fase akut seperti C-reactive protein (CRP) memperkuat dugaan sepsis. Diagnosis sebelum terapi diberikan (sebelum hasil kultur pasitif) adalah tersangka sepsis.(1,6,9)

Penatalaksanaan
Adapun penatalaksanaan sepsis adalah sebagai berikut: (6,9)
1. Suportif.
Lakukan monitoring cairan, elektrolit, dan glukosa; berikan koreksi jika terjadi hipovolemia, hiponatremia, hipokalsemia dan hipoglikemia. Bila terjadi SIADH (Syndrome of appropriate antidiuretic hormone), batasi cairan. Atasi syok, hipoksia dan asidosis metabolic. Awasi adanya hiperbilirubinemia, lakukan transfuse tukar bila perlu. Pertimbangkan nutrisi parenteral bila pasien tidak dapat menerima nutrisi enteral.
2. Kausatif. 
Antibiotik diberikan sebelum kuman penyebab diketahui. Biasanya digunakan golongan penisilin sepeti ampisilin ditambah aminoglikosida seperti gentamisin. Pada sepsis nosokomial antibiotic dibarikan dengan mempertimbangkan flora di ruang perawatan, namun sebagai terapi inisial biasanya diberikan vankomisin dan aminoglikosida atau sefalosporin generasi ketiga. Setelah didapat hasil biakan dan uji sensitivitas, diberikan antibiotic yang sesuai. Terapi dilakukan selama 10-14 hari. Bila terjadi meningitis antibiotic diberikan selama 14-21 hari dengan dosis sesuai untuk meningitis.
Surviving Sepsis Campaigne pada tahun 2004, merekomendasikan penatalaksanaan sepsis berat, dan syok septic sebagai berikut: (2)
1. Early Goal Directed Therapy (EGDT)
Resusitasi cairan agresif dengan koloid dan atau kristaloid, pemberian obat-obatan inotropik, atau vasopresor dalam waktu 6 jam sesudah diagnosis ditegakkan di unit gawat darurat sebelum masuk ke PICU. Resusitasi awal 20 ml/kgBB 5-10 menit dan dapat diulang beberapa kali sampai lebih dari 60 ml/kgBB cairan dalam waktu 6 jam. Pada syok septic dengan tekanan nadi sangat sempit, koloid lebih efektif daripada kristaloid.
Kristaloid dan koloid dapat dipakai pada syok septic, akan tetapi apabila ditinjau dari segi patofisiologi dan patogenesis sepsis yaitu terdapat kebocoran sel endotel dengan meningkatnya molekul adhesi ICAM-1 dan VCAM-1, koloid yang mempunyai efek menyumpal (sealing effect) dan anti-inflamasi dengan menghambat aktivitas ICAM-1 dan VCAM-1 seperti hidroxyethylstarch molekul sedang (BM 100.000-300.000), direkomendasikan sebagai cairan awal pada sepsis dan syok berat. Apabila mempergunakan kristaloid diperlukan jumlah yang lebih banyak dengan risiko bertambahnya edema interstitial.
Kontroversi timbul masalah pemilihan koloid atau kristaloid untuk ekspansi ruang intravascular. Yang pro-koloid mengatakan bahwa koloid akan mempertahankan tekanan osmotic koloid plasma dan meminimalkan akumulasi cairan interstisial. Kristaloid akan menurunkan tekanan osmotic koloid plasma dan cenderung menimbulkan edema paru. Yang pro-kristaloid mencela biaya dan risiko terapi koloid (reaksi anafilaksis, efek pada koagulasi, akumulasi jaringan, dan efek pada ginjal). Pemberian koloid untuk resusitasi volume maksimal 33 ml/kgBB. Penelitian terdahulu randomized control study oleh Tatty ES pada DSS terbukti bahwa resusitasi awal dengan HES 200.000 dapat menurunkan angka kematian secara bermakna. Peneliti lain Zikria dkk, yaitu pada tikus dengan kerusakan endotel akibat terbakar menunjukkan bahwa fraksi HES 200/0,5 bertndak sebagai penyumpal lebih baik daripada 4 grup control yang menerima albumin 5%, RL dan HES dengan BM <50.000 atau HES BM >300.000. Target resusitasi volume adalah: Tekanan Vena Sentral (TVS) 8-12 mmHg; Tekanan arteri rata-rata (Mean Arterial Pressure/ MAP) sesuai umur, tekanan perfusi normal sesuai umur (tekanan arteri rata-rata/TVS); saturasi vena sentral >70%; perfusi jaringan baik; kesadaran baik; jumlah uri >1 ml/kgBB/jam, laktat serum <2 mmol/L, denyut jantung normal sesuai umur, ekstremitas hangat, perbadaan suhu oesofagus (core) dan suhu jempol kaki > 20C.
2. Inotropik/vasopresor/vasodilator
Apabila terjadi refrakter terhadap resusitasi volume, dan MAP kurang dari normal, diberikan vasopresor; Dopamin merupakan pilihan pertama. Apabila refrakter terhadap pemberian Dopamine, maka dapat diberikan epinephrine atau norepinephrine. Dobutamin dapat diberikan pada keadan curah jantung yang rendah. Vasodilator diberikan pada keadaan tahanan pembuluh darah perifer yang meningkat dengan MAP tinggi sesudah resusitasi volume dan pemberian inotropik. Nitrosovasodilator (ntrogliserin, atau nitropusid) diberikan apabila terjadi curah jantung yang rendah dan tahanan pembuluh darah sistemik yang meningkat disertai syok.
Apabila curah jantung masih rendah, akan tetapi normotensi dan tahanan pembuluh darah sistemik meningkat, maka dipikirkan pemberian phosphodiesterase inhibitor. Vasopresin yaitu ADH, adrenocorticotrophic hormone yang dikeluarkan oleh hipotalamus, sebagai vasokonstriktor pada otot polos pembuluh darah dosis 0,01-0,04 u/menit diberikan pada penderita yang refrakter terhadap vasopresor konvensional dosis tinggi.
3. Extra Corporeal Membrane Oxygenation
ECMO dilakukan pada syok septic pediatric yang refrakter terhadap terapi cairan, inotropik, vasopresor, vasodilator dan terapi hormone. Terdapat 1 penelitian yang menganalisis 12 penderita sepsis meningococcus dengan ECMO, 8 hidup dimana 6 dapat hidup normal sampai 1 tahun pemantauan.
4. Suplemen Oksigen
Intubasi endotrakheal dini dengan atau tanpa ventilator mekanik sangat bermanfaat pada bayi dan anak dengan sepsis berat/syok septic, karena kapasitas residual fungsional yang rendah. Volume tidal 6 ml/kgBB dengan permissive hypercapnea dan posisi tengkurap dapat memberikan oksigenasi jaringan yang baik.
5. Koreksi Asidosis
Terapi bikarbonat untuk memperbaiki hemodinamik atau mengurangi kebutuhan akan vasopresor, tidak dianjurkan pada keadaan asidosis laktat dan pH < 7,15 dengan hemodinamik dan kebutuhan akan vasopresor, dan pengaruhnya terhadap kaluaran pada pH rendah.
6. Terapi Antibiotika
Pemberian antibiotika segera setelah satu jam ditegakkan diagnosis sepsis dan pengambilan kultur darah. Terapi antibiotika empiris spectrum luas dosis inisial penuh, satu atau beberapa obat berdsarkan dugaan kuman penyebab dan dapat berpenetrasi ke daam sumber infeksi. Terdapat hubungan antara pemberian antibiotika yang inadekuat dengan tingginya mortalitas. Pada keadaan dimana fokus infeksi tidak jelas, maka antibiotika harus diberikan pada keadaan penderita mengalami perburukan, status imunologik yang buruk, adanya kateter intravena berdasarkan dugaan kuman penyebab dan tes kepekaan. Antibiotika golongan beta-lactams seperti penicillin, carbapenem seperti meropenem, imipenem, cephalosporin dan aminoglikosida. Extended spectrum Penicillin yaitu carboxy penicillins dan ureido-penicillins diberikan untuk infeksi Pseudomonas aeruginosa atau bakteri gram negative lain. Carboxy penicillins termasuk carbenicillin dan ticarcilin dapat diberikan pada infeksi MRSA dan spesies Klebsiella.
Evaluasi pemberian antibiotika dilakukan sesudah 48-72 jam berdasarkan data klinis dan mikrobiologi dengan mempergunakan antibiotika spectrum sempit untuk mengurangi resistensi bakteri, menurunkan toksisitas dan biaya. Lama pemberian antibiotika 7-10 hari dipandu oleh respon manifestasi klinis.
7. Sumber infeksi
Eradikasi sumber infeksi sangat penting, seperti drainase abses, debridement jaringan nekrosis, alat-alat yang terinfeksi dilepas. Kontrol sumber infeksi harus dilaksanakan secepatnya mengikuti resusitasi volume inisial.
8. Terapi kortikosteroid
Penelitian oleh Annane dkk, pada syok septic dewasa dengan insufisiensi adrenal yang refrakter terhadap vasopresor, hydrocortisone 50 mg etiap 6 jam dan dikombinasi dengan fludrocortisone 50 ug diberikan 7 hari, dapat menurunkan angka kematian absolute sebanyak 15%. Dosis yang direkomendasikan untuk syok septic pediatric adalah 1-2 mg/kgbb (berdasarkan gejala klinis insufisiensi adrenal) sampai 50mg/kg untuk terapi empiris syok septic diikuti dosis sama diberikan 24 jam. Terapi hydrocortisone pada syok septic pediatric perlu diberika pada penderita yang resisten terhadap katekolamin, dan terbukti adanya insuffisiensi adrenal, penderita yang berisiko termasuk syok septic dengan purpura, dengan riwayat pemberian steroid untuk penyakit kronis, atau adanya gangguan pada kelenjar adrenal atau hipofise.
9. Anti-inflamasi
Penelitian mengenai terapi anti-inflamasi pada pediatric masih sangat sedikit, dan dengan sa,pel yang kecil.
10. Granulocyte Macrophage Colony Stimulating Factor (GMCSF)
Penelitian IVIG pada pediatric masih sangat sedikit dengan sample kecil, dilaporkan dapat menurunkan angka kematian.
11. Transfusi Tukar
Transfusi tukar tidak disebut dalam Surviving Sepsis Campaign guidline. Keuntungan transfuse tukar adalah mengeluarkan endotoksin bakteri dan mediator inflamasi, meningkatkan transport oksigen, memperbaiki fungsi granulosit daklam melakukan lisis bakteri dan aktifitas opsonin, memperbaiki koagulopati dan gangguan elektrolit. Penelitian sebanyak 31 studi kasus (1995-1996) pada bayi sepsis yang dilakukan hemofiltrasi, didapatkan angka hidup sebanyak 50%.
12. Terapi suportif
PENUTUP

Mortalitas sepsis berat dan syok septic di Negara sedang berkembang termasuk di Indonesia, masih tinggi, perlu peningkatan kewaspadaan dalam diagnosis dini dan penatalaksanaan yang akurat dan cepat. Dengan lebih memahami akan patofisiologi dan patogenesis sepsis, diharapkan dapat menurunkan angka mortalitas syok septik.(2)
Surviving sepsis Campaign guidelines tahun 2004 untuk penatalaksanaan sepsis berat dan syok septic dapat dipakai dan disebarluaskan di seluruh Indonesia, meliputi: Early Directed Goal Therapy dengan terapi cairan agresif, support inotropik, vasopresor, vasodilator dan mempertahankan hemodinamik dalam waktu 6 jam sesudah ditegakkan Diagnosis, pemberian antibiotika 1 jam sesudah resusitasi volume, source control, intubasi dini dengan atau tanpa ventilator, anti-inflamasi dengan rh-APC, imunoterapi dan imunonutrisi dan terapi suprtif terhadap disfungsi organ ginjal, paru, disfungsi koagulasi, dan saluran cerna.(2)
Pemeriksaan CRP sangat umum digunakan untuk mendiagnosa dan memonitor aktivitas peradangan dan keadaan infeksi. Kadar CRP berkurang pada kondisi dengan terapi kortikosteroid atau terapi lain yang mendepresi sistem immune. CRP juga dapat digunakan untuk memonitor pada pemberian terapi kanker dan infeksi karena kadarnya dapat meningkat dan kembali normal dengan cepat.(6 jam dari awal inflamasi)(1,3) . Pemeriksaan kadar CRP serial sangat berguna dalam evaluasi diagnostik pada bayi-bayi dengan dugaan infeksi.(5)

DAFTAR PUSTAKA
 1. Homeler, Barbara. Sepsis. http://www.emedicine.com

2. Ermin, Tatty. Penetalaksanaan Syok Septik Pada Anak. Dalam: Simposium Nasional Perinatologi dan Pediatri Gawat Darurat. Banjarmasin: IDAI Kalimantan Selatan, 2005

3. Widmann, Frances.K. Protein C-Reaktif. Jakarta: EGC, 1995

4. Nissl, Jan. C-Reactive Protein. http://www.medplus.com

5. Benitz,William.E. Serial Serum C-Reactive Protein Levels in the Diagnosis of Neonatal Infection. http://www.pediatrics.org

6. Yunanto,Ari et al. Sepsis. Dalam : Pedoman Diagnosis dan Terapi. Banjarmasin : Bagian/SMF Ilmu Kesehatan Anak RSUD Ulin-FK UNLAM, 2004

7. Nelson, Waldo E. Sepsis. Dalam : Nelson Ilmu Kesehatan Anak. Jakarta : EGC, 1999

8. Reeves, Glenn. C Reactive Protein. http://www.medplus.com/immunologyHAPS/topic1998.htm

9. Mansjoer A et al. Sepsis. Dalam : Kapita Selekta Kedokteran. Jakarta : Media Aesculapius FKUI, 2000

10. Mirkin. Summary. http://www.drmirkin.com

11. Guyton. Fisiologi Kedokteran. Jakarta: EGC, 1997

12. Ganong. Fisiologi Kedokteran. Jakarta: EGC, 1997


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ANAPHYLACTIC SHOCK ( SYOK ANAFILAKTIK )

Senin, 21 September 2009

BAB I
PENDAHULUAN

Anaphylaxis berasal dari bahasa Yunani, dari 2 kata, ana artinya jauh dan phylaxis artinya perlindungan. Secara bahasa artinya adalah menghilangkan perlindungan. (1, 2) Istilah ini pertama kali diperkenalkan oleh Portier dan Richet pada tahun 1902 ketika memberikan dosis vaksinasi dari anemon laut untuk kedua kalinya pada seekor anjing. Hasilnya, anjing tersebut mati mendadak. (1,2)

Anafilaksis merupakan reaksi alergi sistemik yang berat, yang dapat menyebabkan kematian, terjadi secara tiba-tiba sesudah terpapar oleh alergen atau pencetus lainnya. Reaksi anafilaksis merupakan reaksi alergi akut sistemik dan termasuk reaksi Hipersensivitas Tipe I pada manusia dan mamalia pada umumnya. (3) Reaksi ini harus dibedakan dengan reaksi anafilaktoid. Gejala, terapi, dan risiko kematiannya sama tetapi degranulasi sel mast atau basofil terjadi tanpa keterlibatan atau mediasi dari IgE. (1,2,3,4)
Data yang menjelaskan jumlah insidensi dan prevalensi dari syok dan reaksi anapilaksis saat ini sangat terbatas. Dari beberapa data yang diperoleh di Amerika Serikat menunjukkan sepuluh dari 1000 orang mengalami reaksi anapilaksis tiap tahunnya. Saat ini diperkirakan setiap 1 dari 3000 pasien rumah sakit di USA mengalami reaksi anapilaksis. Sehingga, resiko mengalami kematian sebesar 1% dari yang mengalami reaksi anapilaksis, yaitu sebesar 500-1000 kematian yang terjadi.(5,6,7)
Pada kematian akibat reaksi anafilaksis, onset gejala biasanya muncul pada 15 hingga 20 menit pertama, dan menyebabkan kematian dalam 1-2 jam. Reaksi anafilaktik yang fatal terjadi akibat adanya distress pernafasan akut dan kolaps sirkulasi. (5) oleh karena itu penting sekali memahami dan mengetahui tentang syok anapilaksis.(5,6,7,8)
Dalam referat ini, selain akan dipaparkan aspek klinis dari syok anafilaktik, dan penatalaksanaan terkini serta sedikit pembahasan tentang sudut medikolegalnya akan turut pula disertakan.
BAB II
TINJAUAN PUSTAKA

SYOK ANAFILAKTIK
Definisi
Syok
Syok merupakan kegagalan sirkulasi secara akut sehingga menyebabkan perfusi jaringan tidak adkuat dan cedera pada beberapa organ tubuh.
Sedangkan dengan kata lain syok merupakan kegagalan sirkulasi akut dengan ketidakadekuatan perfusi jaringan yang menghasilkan hipoksia secara umum.
Syok terjadi karena adanya gangguan system kardiovaskullar dan ketidakadekuatan kompensasi untuk mempertahankan perfusi jaringan.(6,8,9)

Terdapat tiga jenis syok yaitu(7,8,9):
a) Syok Cardiogenik
Disebabkan adanya gangguan atau kegagalan dalam pemompaan jantung. Contoh yang paling mudah adalah jika terjadi pada orang dengan gagal jantung, Infark Miaokard dan lain-lain.
b) Syok Distributive
Berkaitan dengan masalah pada pembuluh darah. Dalam hal ini terdapat kegagalan dalam mempertahankan resistensi pembuluh darah. Penyebabnya adalah vasodilatasi dan kerusakan mikrovaskular. Contohnya terjadi pada orang dengan sepsis, cedera spinal, dan anafilaktik.
c) Syok Hipovolumik
Berkaitan dengan hilangnya volume sirkulasi darah dalam tubuh. Misalnya terjadi pada perdarahan dan dehidrasi.
Untuk lebih jelasnya bagaimana terjadinya shok mungkin pendekatan secara fisiologis akan lebih muda untuk dipahami
 Syok disebabkan oleh tekanan darah yang tidak adekuat
Tekanan darah rendah berkaitan dengan ketidakadekatan cardiac out put atau rendahnya resistensi pembuluh darah.
 Rendahnya cardiac out put disebabkan oleh masalah kecepatan denyut jantung dan stroke volume.
 Abnormalitas Stroke volume meliputi: keagalan untuk menerima, kegagalan untuk mengeluarkan, dan ketidakadekuatan volme.
 Rendahnya resistensi pembuluh darah perifer berkaitan dengan masalah vasodilatasi pembuluh darah.

Yang dimaksud dengan shock anafilaktik adalah shock yang terjadi secara akut yang disebabkan oleh reaksi alergik atau reaksi hipersensitif. Sedangkan yang dimaksud dengan reaksi alergik adalah peninggian reaksi fisiologik tubuh terhadap bahan antigen yang memperkuat terjadinya antigen-antibodi. Terdapat pula istilah atopi yang menerangkan bentuk anafilaksis yang terjadi secara familiar akibat alamiah seperti biji-bijian, debu dan makanan dan bila terjadi reaksi anafilaksis dapat menimbulkan asma dan sensitivitas terhadap makanan berupa reaksi urtikaria pada kulit.
Shock anafilaktik terjadi dalam masa beberapa detik atau beberapa menit sesudah pemberian antigen dan menyebabkan terjadinya kegagalan sirkulasi dan respirasi. Shock ini terjadi antara 1-3000 pasien di Amerika dan antibiotik yang paling banyak adalah penisilin yang merupakan kematian terbanyak sesudah obat ini disuntikkan dalam masa 60 menit.
Reaksi anafilaksis artinya againts protection (menghilangkan proteksi). Secara harafiah dapat diartikan terdapat mediator yang dilepaskan oleh sel mast dan sirkulasi basofil dimana bahan ini dapat menyebabkan terjadinya shock. Shock anafilaktik diartikan sebagai suatu reaksi yang cepat karena masuknya benda asing ke dalam tubuh yang sensitif yang terjadi secara segera atau tipe I. Reaksi ini dapat pula terjadi akibat pemberian obat-obatan, darah, plasma, kontras media dan gigitan serangga. Terdapat pula istilah anaphylactoid reaction yang antigennya tidak dapat ditentukan dimana reaksi ini dapat terjadi akibat fisik, olah raga, obat-obatan, dan kaustik. Reaksi alaergi sistemik dapat terjadi secara ringan, moderat, serta berat. Misalnya saja, urtikaria generalisata, angio-odem, dan rhinitis merupakan bukan reaksi anapilaksis.(6,7,8,9)
Efidemiologi
Insidensi dari reaksi anapilaksis secara baku sampai saat ini belum diketahui. Di Amerika Serikat, kematian akibat reaksi anafilaksis sistemik kira-kira 1500-2000 kematian per tahun. Kasus nonfatal lebih sering muncul, yakni sekitar0,2 % dari populasi setiap tahunnya.(4) Prevalensi kunjungan ke bagian kegawatdaruratan kira-kira 2 per 10.000 penduduk sampai 5 per 10.000 penduduk. (8) Neugut et al memperkirakan bahwa 1-15 % dari populasi Amerika Serikat berada dalam risiko mendapatkan reaksi anafilaktik atau reaksi anafilaktoid. Lebih lanjut, mereka memperkirakan rata-rata reaksi anafilaksis akibat makanan adalah 0,0004%, 0,7-10% untuk penisilin, 0,22-1% untuk media radiokontras, dan 0,5-5% untuk gigitan serangga. Frekuensi terjadinya anapilaksis meningkat, lebih dari 500-1.000 kasus fatal dari reaksi anapilaksis tiap tahunnya diperkirakan terjadi di USA.(6,7,9)
Dari studi epidemiologi meperlihatkan tiap tahun sebesar 30/100.000 orang dan 21/100.000 rata-rata insidensinya tiap tahun. Gejala dan tanda yang menyertai, dimana tanda dan gejala kulit (100%), pernapasan (69%), oral dan gastroentistinal (24%), dan kardiovaskuler (41%). Menurut Neugut et al dari hasil surveinya, diperkirakan bahwa antara 3.3 dan 43 milyar orang di USA mempunyai resiko untuk mengalami reaksi anapilaksis. Baru-baru ini diperkirakan antara 1453 sampai 1503 orang meninggal tiap tahunnya akibat anapilaktik atau reaksi anapilaksis (disebabkan makanan 100, penicillin 400, media radiokontras 900, latex 3, getah 40-100). Dari data yang diperoleh menunjukkan bahwa anapilaksis merupakan masalah serious kesehatan di USA.(6,7,8,9)

Etiologi
Zat-zat yang sering menyebabkan terjadinya reaksi anafilaksis dapat dibagi atas (2,3,5-12) :
a. Mediator IgE
Protein ( kelapa, ikan, kerang-kerangan, telur )
Antiserum ( tetanus,dan antitoksin dipteri )
Hormon, enzim ( insulin, vasopressin, paratohormone ,ACTH dan TSH )
Enzim (Tripsin, kimotripsin, penisilinase, streptokinase)
Bisa binatang atau Sengatan lebah penyengat, lebah madu,semut api
Ekstrak alergen
Vaksin (Antilimsofitik Gamma Globulin)
Bahan-bahan tumbuhan (Alang-alang, rumput, pohon)
Bahan-bahan bukan tumbuhan (Kutu, bulu anjing dan kucing, dan hewan uji coba laboratorium
Makanan (Susu, telur, ikan laut, kacang,padi-padian, biji-bijian, gelatin pada kapsul)
Polisakarida
Dekstran dan ferum dekstran

b. Mediator komplemen
Reaksi transfusi dengan defisiensi IgA dan metrotreksat

c. Mediator arakidonat
Aspirin dan NSAID
d. Yang dibebaskan sel mast secara langsung
Opiad, tubokurarin, radiokontras dan hidralasin serta olah raga
e. Golongan protamin dan antibiotika
Golongan Penisilin, amfotericin B, nitrofurantoin, golongan kuinolon
f. Anastesi lokal
Prokain, lidokain
g. Relaksan otot
Suxamethonium, gallamine, pancuronium
h. Vitamin
Thiamin, asam folat
i. Agen untuk diagnostik
Sodium dehidrokolat, sulfobromophthalein
j. Bahan kimia yang berhubungan dengan pekerjaan
Etilen oksida
k. Idiopatik
Melphalan, prokarbazin, klorambusil, hidrokiurea, 5-fluorourasil, busulfan dan mitomisin.

Faktor Risiko(2,3,4,6,7,8)
 Atopi merupakan faktor risiko. Pada studi berbasis populasi di Olmsted County, 53% dari pasien anafilaksis memiliki riwayat penyakit atopi. Penelitian lain menunjukkan bahwa atopi merupakan faktor risiko untuk reaksi anfilaksis terhadap makanan, reaksi anafilaksis yang diinduksi oleh latihan fisik, anafilaksis idiopatik, reaksi terhadap radiokontras, dan reaksi terhadap latex. Sementara, hal ini tidak didapati pada reaksi terhadap penisilin dan gigitan serangga.
 Cara dan waktu pemberian berpengaruh terhadap terjadinya reaksi anafilaksis. Pemberian secara oral lebih sedikit kemungkinannya menimbulkan reaksi dan kalaupun ada biasanya tidak berat, meskipun reaksi fatal dapat terjadi pada seseorang yang memang alergi setelah menelan makanan. Selain itu, semakin lama interval pajanan pertama dan kedua, semakin kecil kemungkinan reaksi anafilaksis akan muncul kembali. Hal ini berhubungan dengan katabolisme dan penurunan sintesis dari IgE spesifik seiring waktu.
 Asma merupakan faktor risiko yang fatal berakibat fatal. Lebih dari 90% kematian karena anafilaksis makanan terjadi pada pasien asma.
 Penundaan pemberian epinefrin juga merupakan faktor risiko yang berakibat fatal.
Patofisiologi
Secara patofisiologis yang memegang peranan penting dalam shock anafilaktik adalah antigen, sel-T, sel plasma dan produksi IgE, resting sel-B, prostaglandin, leukotrin, dan asam arakidonat.(6,7,11,12,13)
Anafilaksis dikelompokkan dalam hipersensitivitas tipe 1 atau reaksi tipe segera (immediate type reaction) oleh Coomb dan Gell (1963), timbul segera setelah tubuh terpajan dengan allergen. Anafilaksis diperantarai melalui ikatan antigen kepada antibodi IgE pada sel mast jaringan ikat di seluruh tubuh individu dengan predisposisi genetik, yang menyebabkan terjadinya pelepasan mediator inflamasi.(3) Urutan kejadian reaksi tipe I adalah sebagai berikut: (1,3)

1. Fase sensitasi yaitu waktu yang dibutuhkan untuk pembentukan IgE sampai diikatnya dengan reseptor spesifik pada permukaan sel mast dan basofil. Alergen yang masuk lewat kulit, mukosa, saluran nafas atau saluran pencernaan yang ditangkap oleh makrofag. Makrofag segera mempresentasikan antigen tersebut kepada limfosit T yang akan mensekresikan sitokin (IL-4, IL-3) yang menginduksi limfosit B berfloriferasi menjadi sel plasma (plasmosit). Plasmosit akan memproduksi IgE spesifik untuk antigen tersebut. IgE ini kemudian terikat padareseptor permukaan sel Mast (Mastosit) dan Basofil.
2. Fase aktivasi yaitu waktu yang diperlukan antara pajanan ulang dengan antigen yang sama dan sel mast melepas isinya yang berisikan granul yang menimbulkan reaksi.
3. Fase efektor yaitu waktu terjadinya respon yang kompleks (anafilaksis) sebagai efek mediator-mediator yang dilepas selmast.
Sensitisasi yang diikuti oleh reaksi dapat merupakan reaksi sendiri atau kombinasi dengan hapten, sintesis IgE atau dapat pula terikat pada permukaan sel mast atau bisofil. Pada re-exposure antigen terikat IgE, dipermukaan sel dapat terjadi degranulasi sel mast sehingga dibebaskan histamin, slow-reacting substance of anaphylaxis (SRS-A), eosinophilic chemotactic factor anaphylaxis (ECF-A)
Tekanan arteri ditentukan oleh sfingter arteriol. Bila sfingter ini berelaksasi secara sistemik maka terjadilah shock distributif. Ada empat hal yang menyebabkan relaksasi dari sfingter ini yakni karena faktor neural, adanya mediator dalam sirkulasi, defek pada autoregulasi dan karena mediator lokal.6,7,10,12, 14
Secara neural, reseptor stimulasi adrenergik alfa menyebabkan vasokontriksi akan tetapi stimulasi adrenergik beta vasodilatasi. Adanya zat mediator di dalam sirkulasi seperti katekolamin, angoitensin dan mediator inflamasi menyebabkan tonus vaskuler sistemik menurun. Sementara hormon glukokortikoid menambah sensitivitas terhadap katekolamin. Autoregulasi terutama terdapat sebagai mekanisme pembuluh darah ginjal dan otak untuk mempertahankan pengaliran darah ke kedua organ ini bila terjadi penurunan tekanan darah sistemik. Mediator lokal mungkin sebagai pertahanan terakhir pembuluh darah. Zat-zat seperti kalium, hidrogen, adenosin, karbon dioksida dan asam laktat yang dihasilkan oleh sel dapat menyebabkan vasodilatasi. Bila terjadi pengurangan resistensi vaskuler secara sistemik ( SVR ) menyebabkan tekanan darah meningkat. 6,7,10,12, 14
Antigen merangsang sel B untuk membentuk IgE dengan bantuan sel Th2. IgE diikat oleh sel mast dan basofil melalui reseptor Fc. Sel mast banyak ditemukan pada jaringan ikat di bawah permukaan epitel, termasuk pada jaringan submukosa traktus gastrointestinal, traktus respiratorius, dan pada lapisan dermis kulit. Apabila tubuh terpajan ulang dengan antigen yang sama, maka antigen tesebut akan diikat oleh IgE yang sudah ada pada permukaan sel mast/basofil. Akibat ikatan antigen IgE, sel mast/basofil mengalami degranulasi dan melepas mediator antara lain histamin, leukotrien, dan prostaglandin.(3)Respon fisiologis terhadap mediator tersebut antara lain spasme otot polos pada traktus respiratorius dan gastrointestinal, vasodilatasi, peningkatan permeabilitas vaskular, dan stimulasi ujung saraf sensorik. Hal tersebut menyebabkan timbulnya gejala klasik anafilaksis seperti flushing (kemerahan), urtikaria, pruritus, spasme otot bronkus, dan kram pada abdomen dengan nausea, vomitus, dan diare. Hipotensi dan syok dapat tejadi sebagai akibat dari kehilangan volume intravaskular, vasodilatasi, dan disfungsi miokard. Peningkatan permeabilitas vaskuler dapat menyebabkan pergeseran 50 % volume vaskuler ke ruang extravaskuler dalam 10 menit.(2,3)
Histamin memperantarai efek tersebut di atas melalui aktivasi resptor histamin 1 (H1) dan histamin 2 (H2). Vasodilatasi diperantarai oleh baik reseptor H1 maupun H2. reseptor H2 membeikan efek langsung pada otot polos sementara reseptor H1 menstimulasi sel endotel untuk memproduki NO. Efek pada jantung sebagian besar diperantarai oleh reseptor H2. Resptor H1 secara primer bertanggungjawab untuk kontraksi otot polos extravaskular (misalnya otot bronkus dan otot gasrointestinal). (2)
Reaksi sistemik akut umumnya mulai timbul beberapa menit setelah pemaparan alergen; keterlambatan yang lebih lama dari 1 jam sangat jarang terjadi. Pada kepekaan yang ekstrim, penyuntikan alegen dapat segera menyebabkan keatian atau reaksi subletal dan umumnya reaksi-reaksi yang paling berat terjadi paling cepat.(15)
Para peneliti secara khusus membedakan anafilaksis dengan reaksi anafilaktoid. Dimana keduanya memiliki gejala, penatalaksanaan, dan resiko kematian yang sama, tetapi pada anafilaksis degranulasi sel mast atau basofil selalu diperantarai oleh IgE, sedangkan pada reaksi anafilaktoid degranulasi sel mast atau basofil tidak diperantarai oleh IgE. (3)

Klinis
Reaksi hipersensitivitas secara klasik dapat menimbulkan tiga bentuk yakni(6,7,8,9,11) :
1. Reaksi anafilaksis, dimana reaksi terjadi beberapa detik atau beberapa menit baik lokal maupun sistemik sesudah antigen memasuki tubuh. Bentuk reaksi antigen-antibody ini dapat terjadi begitu antigen memasuki tubuh atau dapat pula terjadi sesudah 30 menit dan dapat pula terjadi terlambat sesudah terjadinya re-exposure antigen (sesudah masuk antigen kedu kalinya). Bentuk reaksi dapat ringan dalam bentuk urtikaria tetapi dapat pula berat dalam bentuk respirasi distres atau shock.
2. Reaksi artus, yang reaksinya dalam bentuk lokal dapat dalam bentuk nekrosis sesudah masuknya antigen.
3. Serum sickness, yang merupakan reaksi sistemik dengan manifestasi lokal berupa urtikaria, demam, artritis, edema dan nefritis.
Secara klinis dapat terjadi delapan gejala, yakni (2,3,6,7,8,9,11):
1. Gejala permulaan
Berupa sakit kepala, gatal-gatal dan rasa panas.
2. Gejala kulit
Dapat dibagi atas eritematosa, urtikaria yang umum, angiodema, konjungtival, Pallor dan sianosis.
3. Gejala respirasi
Dapat berupa bronkospasme, rinitis, edema paru, dan batuk. Pernafasan memendek, obstruksi, tercekik karena adema epiglotis, stridor, serak, hilangnya suara, wheezing dan obstruksi komplit.
4. Gejala kardiovaskuler
Hipotensi, diaforesis, kabur, sinkope, pada jantung terjadi aritmia dan hipoksia.
5. Gejala gastrointestinal
Mual, muntah, keram abdomen, diare dan disfagia.
6. Gejala susunan saraf pusat
Parastesi, konvulsi, dan koma.
7. Gejala pada darah
Pembekuan yang tidak sempurna.
8. Gejala pada sendi
Dapat berupa artralgia.

Manifestasi klinis
Shock anafilaktik yang terjadi dapat disebabkan oleh antibiotik terutama penisilin, serum, vaksin, sari bunga, anastesi lokal dan gigitan ular. Pemberian oral dapat pula terjadi akibat pemberian yodium dan asetil salisilat. Gejala-gejalanya adalah gatal, urtikari, dispnea, wheezing, sinkope, nyeri abdomen, nausea dan muntah. (2,3,6,7,8,9,11)
Pada pemeriksaan fisis didapatkan ronki, susah bernafas, hipotensi, muka memerah atau pucat dan sionasis.
Shock dapat dibagi atas dua tipe, yaitu (6,7,8,9,11):

1. Tipe I atau anafilaksis, disebabkan oleh reaksi hipersensitivitas. Secara serologis terdapat antigen, antibodi IgE dan terdapat mediator yang dibebaskan oleh sel mast ataupun bisofil. Mediator berupa granula dalam sel mast atau dibentuk sesudah masuknya antigen. Yang bertindak sebagai mediator adalah histamin, prostaglandin D2, leukotrin, yang meliputi C4, D4 dan E4, PAF, tripase, simase, heparin, vasodilatori sitokines, faktor tumor nekrosis dan kondroitin sulfat. Faktor mediator ini menyebabkan permeabilitas kapiler bertambah, dilatasi pembuluh sistemik, vasokontriksi pulmoner, bronkokontriksi, aritmia dan negatif inotropik.
2. Tipe II atau reaksi anafilaktoid, sama dengan reaksi anafilaksis akan tetapi tidak terdapat antibodi IgE. Shock anafilaktik seperti ini disebabkan oleh kontras media, NSAID atau aspirin.
Pada binatang percobaan bentuk-bentuk shock anafilaktik bervariasi mulai dari bentuk yang paling ringan sampai ke berbagai bentuk aspiksi yang disebabkan oleh bronkokonstriksi, gejala traktus digestifus berupa muntah dan diare, kongesti pada hati sampai dengan gejala hipotensi. Pada darah terjadi neutropenia, trombositopenia, masa pendarahan yang panjang dan penurunan serum komplemen. Pada manusia kegagalan sirkulasi dan repirasi merupakan penyebab kematian yang utama. (2,3,6,7,8,9,11)
Pada reaksi anafilaksis yang berat reaksi dapat segera terjadi dan kematian dapat terjadi beberapa menit sesudah terjadinya reaksi anafilaksis. Pada reaksi antigen-antibodi sesudah terjadinya reaksi sensitized complex maka dapat dibebaskan berbagai intermedia antara lain histamin yang menyebabkan terjadinya dilatasi arteriolar, serotonin menyebabkan terjadinya konstuksi venula, dan SRS-A yang menyebabkan terjadinya kontriksi bronkial dan bradikinin. (2,3,6,7,8,9,11)
Secara klinis kecurigaan terhadap shock anafilaktik adalah bila terjadi nadi ireguler atau tidak teraba, distres respirasi, sianosis, serak, stridor dan difagia yang disebabkan oleh edema laring. Keluhan pernafasan dapat berupa hilangnya suara pernafasan, batuk, wheezes, di samping urtikaria, angiodema atau edema konjungtiva. Akan tetapi tanda yang khas terjadinya reaksi anafilaksis yang cepat sesudah kontak dengan antigen dan terjadi secara progresif. Pemeriksaan forensik ditujukan pada edema paru, kongesti peribronkial, submukosal edema, perangkap udara, sekresi bronkial intraluminal dan infiltrat eosinofilik pada hipofaring, trakea dan paru. Pemeriksaan posmortem selalu diarahkan pada paru. (2,3,6,7,8,9,11)
Reaksi anafilaksis dapat dilihat dalam bentuk urtikaria, angiodema, obstruksi respirasi sampai dengan kolaps pembuluh darah. Urtikaria adalah bentuk paling penting yang terjadi pada reaksi anafilaksis. Di samping itu terdapat pula bentuk lainnya, seperti rasa takut, kelemahan, keringat dingin, bersin, rinorhea, asma, rasa tercekik, disfagia, mual dan muntah, nyeri abdomen, inkontinensia, sampai dengan kehilangan kesadaran. Akan tetapi vasodilatasi, hipotensi dan shock merupakan trias yang sering terjadi sebagai reaksi anafilaksis. Komplikasi jantung dapat berupa aritmia, gagal jantung, iskemia, stroke, bahkan sampai kematian. Telah dilaporkan pula terjadinya DIC. Walaupun demikian, sebab kematian utama dari anafilaksis adalah shock dan obstruksi saluran pernafasan. Obstruksi saluran pernafasan dapat berupa edema laring, bronkospasme dan edema bronkus dan dapat pula terjadi dalam bentuk shock-lung syndrome. (2,3,6,7,8,9,11)

a. Onsetnya mendadak dan gejalanya progresif
o Pasien akan merasa dan terlihat tidak tenang.
o Reaksi yang hebat berlangsung hanya beberapa menit. Bisa juga reaksi onsetnya berlangsung lambat.
o Waktu onset reaksi anapilaksis dipengaruhi dan tergantung oleh faktor pencetus.
o Onset reaksi nya pada jalur intravena lebih cepat dibandingkan dengan jalur lain termasuk lewat oral.
o Pasien selalu terlihat cemas.

b. Life-threatening Airway dan Breathing dan maslah Circulation
pasien biasanya sering mengalami maslah pada A atau B atau C terjadi bersamaan. Sehingga perlu penanganan yang tepat pada ABCDE nya.
Masalah Airway:
 Pembengkakan jalan napas (Airway swelling), misalnya pembengkakan lidah (pharyngeal/laryngeal edem). Pada pasien bisanya kesulitan dalam bernapas.
 Suara ngorok.
 Stridor – suara ini terdengar sangat keras pada saat suara inspirasi dimana disebabkan oleh sumbatan jalan napas atas.
Breathing problems:
 Shortness of breath – increased respiratory rate.
 Wheezing.
 Patient becoming tired.
 Kejang yang disebabkan karena hypoxia.
 Cyanosis (terlihat kebiruan) – ini biasanya gejala lanjut.
 Gagal nafas.
Masalah Circulation:
 Tanda-tanda dari syok yaitu pucat dan dingin.
 Takikardi.
 Tekanan darah turun (hypotension) – feeling faint (dizziness), kolaps.
 Derajar kesadaran turun atau hilang kesadaran.
 Anapilaksis dapat menyebabkan myocardial ischaemia dan gambaran electrocardiograph (ECG) yang memperlihatkan ketidaknormalan.
 Cardiac arrest.
Masalah sirkulasi (sering menyertai syok anapilaksis) dapat dapat menyebabkan langsung myocardial depression, vasodilatasi dan gangguan capillar, dan kehilangan cairan dari sirkulasi. Bradycardia (pulse yang lambat) biasanya selalu terjadi belakangan, sering terjadi sebelum atau menandai akan terjadi cardiac arrest. Setelah masalah Airway, Breathing dan Circulation sudah dapat dikusai dan ditangani baru setelah itu status neurologisnya dinilai (Disability problems) sebab bisa saja terjadi perfusi jaringan otaknya menurun.10
c. Perubahan kulit dan atau mucosa
Penanganan pada bagian yang mengalami Exposure sambil melakukan penanganan ABCDE.
 Perubahan pada kulit dan mukosa selalu menyertai dari reaksi anapilaksis yaitu lebih dari 80%.
 Biasanya terjadi secara luas.
 Perubhan itu bisa terjadi pada kulit, mukosa, atau keduanya.
 Perubahan tersebut biasanya dalam bentuk gambaran erythema – a patchy, atau generalisata, bisa juga dalam bentuk ruam merah.
 Dapat juga dalam bentuk urticaria yang ditemukan diseluruh tubuhnya. Biasanya dirasakan sangat gatal sekali.
 Angioedema
Walaupun terjadi perubahan pada kulit dengan gambaran menakutkan atau membuat stress pasien, tetap penanganan pada kulit dan mukosa setelah masalah life-threatening airway, breathing dan circulation problems dapat teratasi.10

Pemeriksaan Labolatorium
Peningkatan hematokrit umumnya ditemukan sebagai akibat dari hemokonsentrasi karena peningkatan permeabilitas vaskuler. Serum tryptase sel mast biasanya meningkat. (2,3,6,7,8,9,11)
Diagnosis Banding
Keadaan anafilaksis harus di DD dengan asma yang akut, sinkope vasovagal, tensi pnemotorak ventil, edema paru, aritmia jantung, infark miokard, shock kardiogenik, aspirasi bolus, emboli paru, kejang, keracunan obat akut, shock septik dan shock toksik.
Beberapa keadaan dapat menyerupai reaksi anafilaktik, seperti(6,7,8,9,11) :
1. Reaksi vasovagal
Reaksi vasovagal sering dijumpai setelah pasien mandapat suntikan. Pasien tampak pingsan, pucat dan berkeringat. Tetapi dibandingkan dengan reaksi anafilaktik, pada reaksi vasovagal nadinya lambat dan tidak terjadi sianosis. Meskipun tekanan darahnya turun tetapi masih mudah diukur dan biasanya tidak terlalu rendah seperti anafilaktik.
2. Infark miokard akut
Pada infark miokard akut gejala yang menonjol adalah nyeri dada, dengan atau tanpa penjalaran. Gejala tersebut sering diikuti rasa sesak tetapi tidak tampak tanda-tanda obstruksi saluran napas. Sedangkan pada anafilaktik tidak ada nyeri dada.
3. Reaksi hipoglikemik
Reaksi hipoglikemik disebabkan oleh pemakaian obat antidiabetes atau sebab lain. Pasien tampak lemah, pucat, berkeringat, sampai tidak sadar. Tekanan darah kadang-kadang menurun tetapi tidak dijumpai tanda-tanda obstruksi saluran napas. Sedangkan pada reaksi anafilaktik ditemui obstruksi saluran napas.


4. Reaksi histeris
Pada reaksi histeris tidak dijumpai adanya tanda-tanda gagal napas, hipotensi, atau sianosis. Pasien kadang-kadang pingsan meskipun hanya sementara. Sedangkan tanda-tanda diatas dijumpai pada reaksi anafilaksis.
5. Carsinoid syndrome
Pada syndrom ini dijumpai gejala-gejala seperti muka kemerahan, nyeri kepala, diare, serangan sesak napas seperti asma.
6. Chinese restaurant syndrome
Dapat dijumpai beberapa keadaan seperti mual, pusing, dan muntah pada beberapa menit setelah mengkonsumsi MSG lebih dari 1gr, bila penggunaan lebih dari 5gr bisa menyebabkan asma. Namun tekanan darah, kecepatan denyut nadi, dan pernapasan tidak berbeda nyata dengan mereka yang diberi makanan tanpa MSG.
7. Asma bronchial
Gejala-gejalanya dapat berupa sesak napas, batuk berdahak, dan suara napas yang berbunyi ngik-ngik. Dan biasanya timbul karena faktor pencetus seperti debu, aktivitas fisik, dan makanan, dan lebih sering terjadi pada pagi hari.
8. Rhinitis alergika
Penyakit ini menyebabkan gejala seperti pilek, bersin, buntu hidung, gatal hidung yang hilang-timbul, mata berair yang disebabkan karena faktor pencetus, mis. debu, terutama di udara dingin.dan hampir semua kasus asma diawali dengan RA
.
Terapi
Yang terpenting adalah prevensi dari setiap pencetus, resusitasi kardiopulmoner, penggantian cairan dan membebaskan mediator. Dalam keadaan akut diberikan epinefrin, torniket, infus intravena, cairan antihistamin, intubasi dan trakeostomi; dan pasien harus dirawat di ICU.
Pada prinsipnya terapi dibagi atas :
a. Usaha preventif
b. Usaha pengatasan anafilaksis
Usaha preventif
Hindari faktor alergen seperti makanan. Alergi terhadap makanan 8% pada anak-anak, dan 1-2% pada dewasa, yakni antara lain terhadap kacang, telur, susu dan ikan. Selain itu beberapa hal yang dapat memungkinkan terjadinya anafilaksis adalah suntikan penisilin anestesi lokal, rontgen radio-kontras, latek, idiopatik, angiotensin konverting inhibitor dan sebab lain.
Preparat yang paling sering di rumah sakit mengakibatkan shock anafilaktik adalah beta-laktam terutama penisilin G. Tetapi antara 5-16,5% pasien yang alergi terhadap penisilin mengalami alergi pula terhadap sefalosporin. Tes kulit tidak memberikan jaminan karena yang alergi terhadap penisilin hanya 15-40% yang positif terhadap tes kulit. Pada bisa ular dapat dilakukan tes desensitasi bila tes alergi positif.
Untuk menghindari reaksi anafilaksis dapat dilakukan dua hal, yaitu mengadakan tes kulit dan desensitasi, disamping mencari hubungan kausa alergi.
Karena angka mortalitas tinggi maka yang terpenting adalah prevensi. Untuk prevensi dapat dilakukan :
1. Tes kulit dapat berguna untuk antibiotik beta-laktam, bisa ular, anatesi lokal, insulin, kimopapin, dan berbagai bahan makanan. Karena reaksi anafilaksis dapat terjadi sekalipun hanya dengan tes kulit maka harus di bawah pengawasan yang ketat.
2. Riwayat penyakit dan riwayat reaksi terhadap IgE dari pemberian antigen. Dalam riwayat penyakit ini harus harus dicurigai pula terdapatnya cross sensitif terhadap obat yang lain.
3. Riwayat terdapatnya penggunaan beta-blocker dapat menyebabkan resiko terhadap anafilaksis lebih tinggi dan refraktor terhadap pengobatan.
Pada pemeriksaan laboratorium didapat kadar histamin yang tinggi, rendahnya serum komplemen dan berkurangnya kadar kinogen yang mempunyai berat molekul yang tinggi.

Usaha pengatasan
Usaha pengatasan anafilaksis sama dengan shock lainnya, yaitu(2,3,6-9,11,12,14) :
1. Lindungi jalan nafas (airway=A), pernafasan (breathing=B) dan sirkulasi (circulation=C).
2. Gunakan epinefrin yang merupakan drug of choice. Injeksi 0,5 cc epinefrin/1000 segera mungkin yang dapat diberikan SC, IM atau IV 0,3-0,5 cc (0,3-0,5 mg dalam pengencer 1:1000). Pemberian epinefrin ini dapat dilanjutkan (1:1000) 0,2-0,5 subkutan atau intramuskuler sampai dengan 3 dosis dengan interval 1-5 menit. Atau dapat pula diberikan 0.5-1 mg intramuskuler atau 0,5 mg yang diencerkan, diberikan dalam waktu 5 menit yang diikuti dengan infus terutama bila terjadi hipotensi.
3. Ulangi injeksi epinefrin bila perlu setiap 10-20 menit, disamping itu kalau tempat injeksi dapat dialokasir dapat diberikan secara subkutan dosis yang sama 0,1-0,2 mg pada tempat injeksi. Secara umum diberikan (a) difenhidramin 1,25 mg/kg maksimum 50 mg IV atau IM, (b) hidrokortison 200 mg atau metilprednisolon 50 mg IV setiap 6 jam selam 24-48 jam, dan (c) simetidin 300 mg IV sesudah 3-5 menit.
4. Bila terjadi hipotensi harus diberikan (a) epinefrin (1:1000) 1 ml dalam 500 ml NaCI 0,9% 0,5-2,0 ml/min atau 1-4 g/min, via vena sentral, (b) NaCI 0,9 %, Ringer laktat atau larutan osmotik koloid, (c) levarterenol bitartrat 4 mg dalam 100 cc dalam dektrosa 5% dengan dosis 2-12 g/min IV, (d) glukagon, jika pasien menerima terapi -blocker, 1 mg/ml IV bolus atau infus 1 mg/liter dektrose 5% dengan kecepatan 5-15 ml/min.
5. Bila shock akibat injeksi di tangan terutama karena vaksinasi, pasang torniket pada daerah yang proksimal dan berikan epinefrin 0,1-0,3 cc pada tempat injeksi.
6. Bila terjadi adema laring, berikan epinefrin intravena (IV) dan bronkospasme. Dapat pula berikan 1 cc (0,1 mg) epinefrin dalam larutan 10 cc NaCI 0,9% intravena secara perlahan-lahan lebih dari 5 menit. Dosis ini dapat diulangi sekali atau dua kali tiap 10 menit. Pertimbangkan pula pemberian infus dengan dosis permulaan 0,5-10 g/menit bila terjadi hipotensi. Untuk obstruksi laring dilakukan pula intubasi endotrakeal, krikotiroidotomi, trakeostomi, oksigen dan ventilasi mekanis.
7. Bila terjadi bronkokontriksi, berikan (a) suplemental oksigen, melalui hidung atau mulut 5-10 liter /menit bila tidak bia persiapkandari mulut kemulut (b) aminofilin, bila pasien tidak dalam shock, berikan 5 mg/kg sampai 500 mg IV lebih dari 20 menit kemudian 0,3-0,8 mg/kg/jam IV, (c) metaproterenol (5%) 0,3 ml dalam 2,5 ml NaCI atau albuteral (0,5%) 0,5 ml dalam 0,2 ml epinefrin secara nebulizer, dan (d) isoproterenol jika pasien refrakter terhadap semua obat dengan dosis 0,0375 g/kg/min IV ditambah secara pelan 0,225 g/kg/min.
8. Untuk pasien-pasien yang menderita penyakit kardiovaskuler, diabetes melitus, tiroid dan arteriosklerosis serebral dapat diberikan setengah dosis dan harus dievaluasi kemungkinan terjadinya hipertensi.
9. Pertimbangkan intubasi atau krikotiroidotomi dan berikan oksigen yang tinggi.
10. Harus dihentikan pemberian antigen yang menyebabkan anafilaksis.
11. Pemberian antihistamin dapat menghambat efek mediator dan merupakan pilihan sesudah epinefrin dan harus dikombinasi antara H1-blocking antihistamin (difenidramin ) 50 mg IV ( kerana H1 saja dapat merugikan reaksi anafilaksis ) dan H2-blocking antihistamin ( simetidin ) 300 mg IV tiap 6 jam dan ranitidin 50 mg IV tiap 6-8 jam.
12. Pengatasan hipotensi dapat menurut skema shock 1 liter kristaloid ( NaCI atau Ringer laktat ) tiap 20-30 menit. Di samping itu pertimbangkan pula pemberian kortikosteroid, metilprednisolon 125 mg atau hidrokortison 250 mg IV dan dapat diulangi tiap 6-8 jam.
13. Pada pasien dengan keluhan anafilaksis yang ringan harus diobservasi selama 3-8 jam dan diberikan difendramin 25-50 mg oral dalam masa 6-8 jam sampai beberapa hari.
Gambar 2. Alogaritma penanganan syok anapilaksis10
Monitoring (2,3,6-9,11,12,14)
 Observasi ketat selama 24 jam, 6 jam berturut-turut tiap 2 jam sampai keadaan fungsi membaik
 Klinis : keadaan umum, kesadaran, vital sign, produksi urine dan keluhan
 Darah : Gas darah
 EKG

Prognosis
Anaphylaxis may occur following re-exposure to the inciting agent. Rates of recurrence vary with the nature of the inciting agent and host factors. Other than the possibility of recurrence or the occurrence of complications, anaphylaxis carries no long-term effects. 2,3,6-9,11,12,14
Kematian Pada Syok Anafilaktik
Kematian pada syok anafilaktik kebanyakan disebabkan oleh kolapsnya jantung dan edema laring oleh obat-obatan, makanan, dan gigitan serangga. Gejala yang timbul pada serangan anafilaksis antara lain pusing, gatal pada kulit, urtikaria, sesak nafas, wheezing, kesulitan dan kegagalan pernafasan. Pada kematian karena anafilaksis, munculnya gejala biasanya berlangsung pada 15-20 menit pertama. Saat pasien meninggal sangat dibutuhkan dokumen (medical record) yang baik tentang perkembangan penyakit pasien mulai dari gejala terjadinya reaksi anafilaksis sampai pasien meninggal. Kematian biasanya terjadi dalam waktu 1-2 jam. Beberapa serangga seperti salah satu jenis semut, bisa yang dihasilkan sangat toksik dan kematian terjadi tanpa berlangsungnya reaksi anafilaktik jika gigitannya banyak. (16)
Reaksi anafilaksis yang fatal menyababkan terjadinya acute respiratory distress atau circulatory collapse. Obstruksi pada saluran pernafasan bagian atas dapat disebabkan oleh edema laring dan pharing. Pada saluran pernafasan bagian bawah disebabkan oleh bronkospasme dengan kontraksi dari otot-otot pernafasan, vasodilatasi dan peningkatan permeabilitas kapiler. Henti jantung mungkin disebabkan karena terhentinya pernafasan, Efek langsung oleh mediator kimia pada syok anafilaksis disebabkan oleh hilangnya cairan intravascular oleh edema dan vasodilatasi.(16)
Dalam satu kepustakaan dituliskan Pumphrey dan Roberts melakukan autopsi pada 56 kasus kematian syok anafilaksis. Didapatkan 16 kasus disebabkan oleh alergi makanan karena kesulitan bernafas dengan 13 kasus karena henti nafas. Sebaliknya, syok tanpa kesulitan bernafas ditemukan pada 9 dari 19 kasus karena sengitan serangga dan 12 dari 21 kasus karena reaksi iatrogenik.(16)
Pada autopsi, hal-hal yang bisa ditemukan tidak spesifik. Seringkali didapatkan edema laring, tetapi jarang didapatkan obstruksi komplit dari saluran pernafasan. Pumphrey dan Roberts melaporkan edema laring dan pharing masing-masing didapatkan 8% dan 49%. Emfisema yang disebabkan oleh bronkokonstriksi bisa ditemukan. Kongesti pulmonal dan visceral, edema, dan perdarahan pulmonal bisa didapatkantetapi tidak spesifik. Pada penelitian yang dilakukan oleh Pumphrey dan Roberts, 23dari 56 kematian karena anafilasis tidak ditemukan kelainan kelainan makroskopik pada autopsi.(16)
Untuk membuat diagnosis adanya reaksi anafilaksis ditentukan adanya riwayat alergi atau ada yang menyaksikan seseorang meninggal karena sengatan serangga, makanan dan obat-obatan. Kebanyakan kematian yang berhubungan dengan obat-obatanyaitu penggunaan penicillin atau agen iodine-containing contrast yang digunakan untuk tujuan diagnosis. Petunjuk penggunaan agen low-osmolar pada radiologi dapat mengurangi jumlah reaksi membahayakan yang bisa timbul karena agen iodinated contrast.(16)
Pada kematian yang disebabkan oleh gigitan serangga, adanya elevasi dari venom-spesifik IgE antibody dapat dideteksi pada darah postmortem. Elevasi level dari IgE spesifik antibody tidak selalu mengindikasikan terjadinya reaksi anafilaktik, kecuali jika seseorang memang sensitif dengan venom (bisa) tersebut. Ditemukannya antibodi dapat menjelaskan terjadinya reaksi anafilaksis karena gigitan serangga. Tidak semua kematian karena reaksi anafilaksis menunjukkan adanya antibodi yang spesifik dengan serangga yang menggigitnya. Pada beberapa kasus, cross-reaction dengan antigen pada serangga lainnya yang bisa menyebabkan kematian karena alergi masih memungkinkan.(16)
Aspek Etika dan Medikolegal
Reaksi alergi yang bisa timbul tidak sama pada setiap orang, bisa ringan berupa gatal yang hilang dengan sendirinya, bisa pula berat hingga fatal. Reaksi alergi terhadap obat muncul tanpa diduga. Seseorang yang tadinya tidak apa-apa minum Antalgin, suatu ketika gatal sekujur tubuhnya setelah minum antalgin. Jangka waktu munculnyapun bisa cepat bisa lambat, demikian pula berat ringannya. Seseorang mungkin langsung syok tak sadarkan diri sesaat setelah minum antalgin, misalnya.(17) Sementara yang lain hanya gatal, beberapa saat kemudian hilang gatalnya. Berikut beberapa contoh kasus pasien dengan reaksi alergi :
 Seorang penderita mendapatkan obat. Beberapa saat kemudian penderita tersebut datang lagi dengan keluhan gatal setelah minum obat, yang kemungkinan menandakan reaksi alergi. Pada kasus ini, seorang dokter wajib memberikan catatan tertulis reaksi alergi obat kepada penderita. Tidak cukup hanya mengatakan bahwa si penderita alergi terhadap obat A. Catatan diberikan kepada penderita disertai pesan agar menyerahkan catatan alergi tersebut kepada dokter manapun jika sewaktu-waktu sakit. Selain memberikan catatan riwayat alergi kepada penderita, dokter tersebut wajib mencatat dalam rekam medik.(17)
 Seorang penderita membawa satu tas berisi obat minum, obat suntik dan suntikan kecil, disertai surat dari dokter ahli agar penderita diinjeksi obat secara berkala selama waktu tertentu (kasus penderita TBC berulang). Dalam surat disebutkan agar penderita ditest (test kulit) terlebih dahulu menggunakan pengenceran tertentu. Siapa sangka, ketika test sedang berlangsung (belum sampai tuntas test kulit), tiba-tiba penderita syok (anafilaktik syok). Tak sadarkan diri, ngorok, nadi tak teraba, napas megap-megap. Setelah tindakan darurat penanganan anafilaktik syok sesuai prosedur tetap (protap), penderita dapat diselamatkan. (17)
 Seorang pasien berobat ke dokter kemudian padasaat pasien diterapi dengan suntikan pasien tiba-tiba kolaps akibat obat suntik yang diberikan atau yang biasa disebut anafilaktik syok. Dalam hal ini dokter perlu melawan reaksi tersebut dengan memberikan penanganan berupa pemberian kortikosteroid atau kalau perlu pemberian adrenalin. Namun dokter tersebut tidak memberikan obat tersebut karena alasan obat tersebut tidak ada sehingga pasien tersebut meninggal dunia. Maka dokter tersebut dapat dipidana karena kealpaan dan kelalaiannya menyebabkan hilangnya nyawa seseorang.(18,19)
Adapun aspek medikolegal pasien dengan anafilaktik yaitu: (1,2,18,19)
 Keterlambatan menganggap/madiagnosis pasien tersebut mengalami anafilaktik padahal sudah terjadi sinkop dan hipotensi sehingga tidak diberikan penanganan yang cepat dan tepat.
 Tidak menganamnesa penyakit alergi yang diderita pasien sebelumnya sebelum terapi diberikan (obat, makanan, atopi)
 Kelalaian memeberikan resep injeksi epinefrin dan penjelasan kepada pasien tentang penyimpanan dan penggunaannya.
 Kegagalan mendiagnosis penyebab terjadinya anafilaktik
 Tidak mencegah terjadinya reaksi obat pada pasien yang diketahui hampir atau sensitif dengan melakukan tes terlebih dahulu (cross-reacting drug).
 Lalai memberikan informed consent sebelum melakukan tindakan pada pasien
 Tidak memberikan penanganan yang tepat (sesuai prosedur penanganan syok anafilaktik)
 Tidak bersiaga dengan menyediakan emergency kit bila melakukan injeksi.

BAB III
PENUTUP

Kesimpulan
Anapilakis merupakan reaski sitemik, yang merupakan reaski alergi tipe I yang sering berakibat fatal. Reaksi Anapilaksis dapat disebabkan oleh beragam macam sebab, diantaranya makanan, latex, obata-obatan, reaksi sengatan serangga serta masih banyak penyebab lainnya.
Pemberian epineprin dengan segera merupakan penanganan yang sangat penting dalam penatalaksanaan syok anapilaksis. Dan beberapa penatalaksanaan tambahan diantaranya H1 dan H2 reseftor agonis, kortikosteroid, dan bronkodilator, hanya saja pemberiannya tidak dapat menggantikan epineprin. Pasien dengan riwayat reaski anapilaksis harus di berikan edukasi tentang kondisi, khususnya dengan memperhatikan untuk mencegah faktor yang sudah diketahui dapat mencetuskan reaksi anapilaksis pada tubuhnya. Serta dianjurkan setiap pasien untuk memiliki dan diajarkan cara menggunakan epineprin secara auto injeksi (menginjeksi sendiri) dan melakukan konsultasi kepada orang lain setiap waktu.

DAFTAR PUSTAKA

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