Alison Morris
Kristina Crothers
Laurence Huang
Human immunodeficiency virus (HIV)-infected patients require critical care for various reasons that may or may not be related to their underlying immunodeficiency. The evaluation of HIV-infected persons admitted to the intensive care unit (ICU) requires consideration of all processes that can occur in HIV-uninfected persons, as well as those particular to HIV infection, namely opportunistic infections, neoplasms, and HIV-associated comorbidities or toxicities associated with antiretroviral therapy. Management of acute, life-threatening conditions requires institution of similar therapies in HIV-infected persons as in HIV-uninfected persons, with awareness of potential drug toxicities and drug interactions that can occur in those on antiretroviral therapy.
This chapter reviews the critical care of HIV-infected patients, including causes of ICU admission and patient outcomes. Special emphasis is placed on the etiology and management of respiratory failure, particularly that due to Pneumocystis pneumonia (PCP), which carries an especially high mortality risk. The potential impact of highly active antiretroviral therapy (HAART) on the critical care of HIV-infected patients is summarized, and issues regarding HIV testing and decreasing transmission of HIV in the health care setting are discussed.
Epidemiology of Hiv-Infected Patients In the Icu
ICU Admission Rates and Outcomes
The first cases of HIV/AIDS were reported in 1981. Since that time, there have been many developments in the treatment of HIV and its associated diseases, most notably the introduction of HAART in 1996. Rates of ICU admission and mortality related to ICU admission for HIV-infected patients have shifted multiple times during the AIDS epidemic. Reasons for these changing patterns are likely related in part to patient and provider attitudes regarding the utility of intensive care (1). A series of investigations focusing on outcomes of HIV-infected patients requiring intensive care at San Francisco General Hospital illustrates these changes. An analysis of ICU admissions during the early 1980s reported mortality rates of nearly 70% for HIV-infected patients, with most patients admitted for PCP (2). Despite increasing hospital admissions of HIV-infected patients after 1984, the rates of ICU admission declined, likely the result of both the physicians' and patients' views of ICU care as futile (1). Subsequently, in the late 1980s, mortality rates decreased coincident with the introduction of adjunctive corticosteroids to treat PCP (3). However, in the early 1990s, ICU mortality increased in the setting of increased rates of ICU use, possibly because of renewed optimism in outcomes (4). Data from the immediate pre-HAART period of 1992–1995 demonstrated an overall improvement in the mortality rate to 37% compared to the early days of the AIDS epidemic (5).
Studies have suggested a further decline in ICU mortality after the introduction of HAART, although this has not been demonstrated in all reports. In studies from San Francisco General Hospital, ICU mortality decreased significantly from 37% in 1992–1995 to 29% in 1996–1999 (1,6). Likewise, studies comparing the mortality rate between 1991–1992 and 2001 from Beth Israel Medical Center in New York demonstrated a decrease in mortality from 51% to 29% (7). In contrast, analyses of ICU admissions at a hospital in Paris, France, found that ICU mortality was unchanged when comparing admissions before and during the HAART era (8,9). Overall, in recent studies, the average reported in-hospital mortality for HIV-infected patients admitted to the ICU ranged between 25% and 40%, with a median ICU length of stay of 5 to 11 days (5,6,7,8,9,10,11,12) (Table 116.1).
Despite decreasing hospitalization rates for HIV-infected patients, ICU admission rates have not changed substantially in the HAART era (6,7,8,9,13). Approximately 5% to 12% of hospital admissions for HIV-infected patients involve ICU care (8,12). Possible reasons why ICU admissions have remained relatively constant include the fact that a large proportion of HIV-infected patients continue to be admitted to the ICU without prior known HIV infection (range 28%–40%) (8,9). In addition, approximately 50% of patients are not on HAART at the time of admission (8,9,12). Thus, these patients may be presenting with critical HIV-associated illnesses, as they have not been receiving care or have not been able to benefit from HAART. Furthermore, as overall survival has improved in HIV-infected patients on HAART, the number of persons living with HIV has increased. Given this improved survival, providers may be more likely to admit patients to the ICU and pursue aggressive life support measures (8,13).
Indications for ICU Admission
Studies of critically ill HIV-infected patients indicate that the spectrum of diseases requiring ICU admission is changing in the setting of HAART. Early in the epidemic, most patients were admitted with an AIDS-associated condition, most often PCP. Increasingly, patients with HIV infection are admitted with a non–AIDS-associated condition. In a study from Beth Israel Medical Center in New York, ICU admissions for non–HIV-related disease increased substantially from 12% of all admissions in 1991–1992 to 67% in 2001 (7). Likewise, in a study from France, the proportion of admissions for non–AIDS-related conditions increased significantly from 42% to 63% when admissions between 1995–1996 and 1997–1999 (9) were compared. Data from San Francisco General Hospital found a similarly high proportion of patients (63%) admitted with non–AIDS-related conditions from 1996 through 1999 (6).
Acute respiratory failure is the most common indication for ICU care, accounting for approximately 25% to 50% of ICU admissions in HIV-infected patients (5,6,9,10,11,12,14,15). Pneumocystis jirovecii was the responsible pathogen in approximately 25% to 50% of these patients in earlier investigations (5,10,16). Although decreased in some studies (7), it remains a significant cause of respiratory failure in recent studies, accounting for 14% to nearly 50% of cases of respiratory failure (6,7,12,17). Bacterial pneumonia is also a frequent cause of acute respiratory failure and in some studies is now as common (6) or more common (7) than PCP.
Sepsis is an increasingly frequent indication for ICU admission, in one study increasing from 3% to 23% of all admissions for HIV-infected patients during recent years (9). Other commonly reported causes of ICU admission include CNS dysfunction (11%–27%), gastrointestinal bleeding (6%–15%), and cardiovascular disease (8%–13%) (5,6,9,10,15,16). Other reasons for ICU admission unrelated to immunodeficiency include trauma, routine postoperative care, noninfectious pulmonary diseases such as asthma and pulmonary embolism, renal failure, metabolic disturbances, and drug overdose. Given the frequent coinfection with hepatitis C among patients with HIV, liver disease may be increasing as a cause of death (18,19), and complications related to cirrhosis often require ICU admission. In addition, solid organ transplantation (liver, kidney) is currently being studied in HIV-infected patients; thus, these patients may also be encountered in the ICU setting.
Predictors of Mortality during ICU Admission
Mortality in the ICU is clearly related to the reason for ICU admission. The highest mortality rates for HIV-infected patients requiring ICU admission are associated with sepsis and respiratory failure. Mortality rates of approximately 50% (5,15), and as high as 68%, have been reported for sepsis (20).
If respiratory failure is due to PCP, mortality remains nearly 50% (6,12) and is increased if complicated by PCP-associated pneumothorax (6,8). For AIDS patients admitted to the ICU for other HIV-related reasons, the reported mortality is generally lower. For example, the reported mortality for CNS dysfunction is 20% to 48% (5,10,11,12,15), whereas the mortality for gastrointestinal disease is approximately 30% to 35% (5,10,11). However, patients admitted with non–HIV-related conditions may have better outcomes. In a study from San Francisco General Hospital, patients admitted with a non–AIDS-associated diagnosis were significantly more likely to survive than patients admitted with an AIDS-associated condition (odds ratio [OR] 2.9, 95% confidence interval [CI] 1.5–5.8, p = 0.002) (6). In a study from New York, ICU admission with an HIV-related illness was independently associated with increased mortality (OR 4.2, 95% CI 2.0–9.0, p <0.001) (12).
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Table 116.1 Mortality associated with ICU admission among HIV-infected patients in the HAART era |
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Mortality during hospitalization is also related to the severity of the acute illness (Table 116.1). Predictors of increased hospital mortality include the need for mechanical ventilation and disease severity (as assessed by scoring systems such as the Simplified Acute Physiology Score I [SAPS I], and the Acute Physiology and Chronic Health Evaluation II [APACHE II] score) (5,6,9,12,15). ICU mortality has also been related to the preadmission health status of the patient. Patients with a decreased serum albumin level or a history of weight loss may also have a higher mortality (5,6,15). The CD4+ T-cell count and the plasma HIV RNA level have generally not been independent predictors of short-term mortality during the ICU stay (5,6,7,11,12,16). However, long-term mortality after ICU admission is related to the underlying severity of HIV disease (5,15,16). Compared to pre-HAART, long-term survival following ICU discharge is improved in the HAART era (8,9).
Impact of Antiretroviral Therapy on ICU Mortality
The full impact of HAART on outcome of HIV patients in the ICU remains unclear, as prospective, randomized trials assessing the initiation of HAART on outcome in critically ill patients have not been completed. Two retrospective studies conducted at San Francisco General Hospital suggest that HAART may improve outcomes in critically ill HIV patients. In a review of all HIV-infected patients admitted to the ICU between 1996 and 1999, patients receiving combination HAART at the time of ICU admission were less likely to present with two conditions associated with decreased survival, an AIDS-associated diagnosis and decreased serum albumin, but HAART itself was not independently associated with survival (6). In a study of all HIV-infected patients with PCP who were admitted to the ICU at San Francisco General Hospital between 1996 and mid-2001, patients who were on HAART at the time of ICU admission or started HAART during hospitalization had an improved survival compared to patients not receiving HAART (21). However, in another study from New York City, ICU mortality was not different in patients admitted between 1997 and 1999 when comparing patients receiving HAART versus those not on HAART (12). Furthermore, the prior use of HAART was not associated with differences in overall hospital mortality or length of stay (12). Another study found that although ICU mortality had improved in recent years, this improvement could not be attributed to HAART because none of the patients received this therapy (22). Conclusions regarding the impact of HAART on outcome are limited by the nonrandomized nature of these retrospective studies and by the inability to measure potential bias in the selection of which patients received HAART. In addition, these studies do not address treatment failure, drug resistance, or medication nonadherence prior to or after ICU admission, all of which influence long-term outcome (12).
Immediate Concerns in Managing Critically Ill Hiv-Infected Patients
The initial management of critically ill HIV-infected patients includes all the immediate concerns in HIV-uninfected patients such as securing a stable airway and ensuring adequate respiration and circulation. The immediate management of patients with respiratory failure depends on the underlying reason for respiratory compromise, but consideration of opportunistic infections is warranted early in the course of care to ensure prompt diagnostic evaluation and initiation of appropriate antibiotic therapy. Management of patients in shock consists of similar strategies as in HIV-uninfected patients and depends on the cause of shock, with use of volume resuscitation, vasopressors, and/or inotropic agents as appropriate to maintain adequate mean arterial pressures and systemic perfusion. For patients with septic shock, early goal-directed therapy should be instituted (23). Given the increased association of HIV with cardiovascular disease, cardiomyopathy (24), and adrenal insufficiency (25), providers should be alert to the possibility that these conditions may also cause shock in HIV-infected patients.
Certain aspects of the patient's history are important for initiating early appropriate management. The degree of immunosuppression related to HIV infection is a critical determinant of risk for opportunistic infections. In addition, use of and adherence to antiretroviral therapy and prophylactic antibiotics, as well as intravenous drug use and exposures to endemic fungi and mycobacteria, are key components of the patient's history. The evaluation and management of the most common indications for ICU admission among HIV-infected patients are discussed in detail below.
Pulmonary Manifestations of Hiv
Spectrum of Respiratory Diseases and Approach to Diagnosis
Although the spectrum of diseases leading to respiratory failure has changed during the HAART era, acute respiratory failure is still the most common cause of ICU admission for HIV-infected patients (5,6,9,10,11,12,14,15). Respiratory failure can occur from a multitude of causes including infections, neoplasms, drug overdose, and neurologic conditions that may be both HIV- and non–HIV-related. Rapid diagnosis and initiation of appropriate therapy is crucial, particularly in patients with HIV-associated infections. Although many of the conditions have typical signs and symptoms, many of the presentations can overlap. Therefore, definitive diagnosis should be pursued whenever possible.
Appropriate workup includes chest radiograph and occasionally chest computed tomography (CT). Blood and sputum cultures should be obtained, and bronchoscopy with bronchoalveolar lavage (BAL) should be strongly considered for definitive diagnosis. In some cases, pulmonary disease becomes disseminated, and biopsy of other sites such as lymph nodes or bone marrow can be useful in obtaining a diagnosis. It is important to remember that all the conditions leading to respiratory failure in the non–HIV-infected patient also occur in those with HIV infection. Diagnoses such as pulmonary embolism, asthma, chronic obstructive pulmonary disease, and cardiogenic pulmonary edema also present with respiratory failure, and appropriate testing should be performed.
Pneumocystis Pneumonia
Pneumocystis pneumonia (PCP) has historically been the most common cause of respiratory failure in AIDS patients (5,10,16). PCP is caused by the organism Pneumocystis jirovecii, formerly Pneumocystis carinii. The numbers of patients admitted to the ICU with PCP has decreased since the introduction of HAART, but it remains an important cause of morbidity and mortality in the HIV-infected ICU patient. In the 1980s, patients with PCP who were admitted to the ICU had a mortality rate as high as 81%, with mortality for those requiring mechanical ventilation approaching 90% (2). The introduction of adjunctive corticosteroids for moderate to severe PCP in the mid-1980s led to an improvement in mortality for PCP-associated respiratory failure to approximately 60% (3,26,27). Since that time, there has been little change in outcomes from severe PCP, with recent studies still reporting a hospital mortality of approximately 60% (5,6). The primary factors that determine mortality in patients with PCP are the need for mechanical ventilation and the development of a pneumothorax. Either of these factors portends a poor prognosis, and the occurrence of both is almost uniformly fatal (6,28). Other factors that have been reported to be associated with mortality in some studies include low serum albumin, admission to the ICU after 3 to 5 days of hospitalization, increased age, and elevated serum lactate dehydrogenase (LDH) (6,22,28,29,30).
Clinical Presentation
PCP is most frequent in patients with a CD4+ cell count below 200 cells/µL, with the risk of PCP increasing as the CD4+ count decreases below that level (31,32). Although use of PCP prophylaxis decreases the incidence of PCP, patients receiving prophylaxis may still develop PCP, especially if severely immunocompromised (33). However, many patients with PCP do not know that they are HIV-infected, and therefore never receive PCP prophylaxis. Recent studies have reported that 28% to 57% of patients admitted to the ICU are diagnosed with PCP as their first manifestation of HIV; thus clinicians need to consider PCP in any patient with a consistent clinical picture if the patient's HIV status is unknown (21,28). HIV-infected patients continue to present with PCP because of a lack of regular medical care, nonadherence to PCP prophylaxis, or failure to have appropriate prophylaxis prescribed (34,35).
Risk factors for PCP other than a low CD4+ cell count, the presence of oropharyngeal candidiasis, and prior PCP are debated. For example, exposure to an infected rodent can result in PCP in immunosuppressed rodents, but whether human exposure increases PCP risk is still unclear (36). Certain activities such as gardening have been associated with increased risk, and there appears to be geographic variation in PCP risk (37,38). The influence of cigarette smoking has also been debated, although some studies have reported an increased risk of PCP in smokers (39,40).
The symptoms of PCP can be nonspecific but include fever, tachypnea, dyspnea, and cough. The cough associated with PCP is most often nonproductive or productive of clear sputum. Patients with purulent sputum are more likely to have bacterial pneumonia. The pace and duration of symptoms is also important in distinguishing PCP from bacterial pneumonia. Unlike in the non–HIV-infected immunosuppressed population, HIV-infected patients with PCP generally report the subacute onset of symptoms over several weeks, with the median duration of symptoms in one study being 28 days (41).
Many patients with PCP have an unremarkable lung examination. They will often manifest hypoxemia and an increased alveolar-arterial oxygen gradient. Laboratory tests can suggest the diagnosis, but are often nonspecific. The white blood cell count can be normal, decreased, or increased. Serum LDH is often elevated in patients with PCP. The test has a sensitivity of 83% to 100%, and a normal LDH does not rule out the diagnosis (42,43,44). Also, multiple pulmonary and nonpulmonary conditions can result in an elevated LDH, so an elevated LDH does not rule in the diagnosis. In general, the LDH is more useful as a prognostic rather than a diagnostic test. The degree of elevation correlates with outcome and response to therapy, and patients with a rising serum LDH in the face of treatment have a worse prognosis (44). The arterial blood gas in PCP demonstrates hypoxemia and a widened alveolar-arterial gradient, which can be seen in any pulmonary disease but is useful in determining the need for adjunctive corticosteroids and ICU care. A recent study examined the utility of serum procalcitonin measurement in distinguishing PCP from tuberculosis and bacterial pneumonia (45). The authors found that procalcitonin levels were significantly lower in PCP than in either TB or bacterial pneumonia, but this test has not been applied in large-scale clinical studies.
The classic chest radiographic appearance of PCP is a diffuse interstitial, reticular, or granular infiltrate (Fig. 116.1). PCP can also result in focal airspace consolidation, although this presentation is less common. Infiltrates are occasionally unilateral or asymmetric and, in patients receiving aerosolized pentamidine for prophylaxis, there may be an upper lobe predominance. In general, the pattern (reticular or granular) is more suggestive of the diagnosis than the distribution. Severe PCP is similar to the acute respiratory distress syndrome (ARDS) in causing widespread capillary leak that results in bilateral infiltrates, and these two entities may be indistinguishable radiographically. Cysts or pneumatoceles occur in about 10% to 20% of patients, and these changes can be seen before, during, or after PCP treatment (46,47). Patients with PCP are at risk for developing spontaneous pneumothoraces, and PCP should be high in the differential for any HIV-infected patient presenting with a pneumothorax. Radiographic findings such as pleural effusions or lymphadenopathy are uncommon in PCP, and their presence should lead the clinician to consider alternate or concurrent diagnoses. High-resolution CT scans can be helpful in demonstrating diffuse ground glass opacities typical of PCP, but these findings are not specific.
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Figure 116.1. Portable chest radiograph from a patient with Pneumocystis pneumonia demonstrating diffuse bilateral infiltrates and pneumothoraces. (Courtesy of Laurence Huang, M.D., M.A.S., Professor of Medicine, University of California, San Francisco.) |
Diagnosis
Although patients may present with typical signs and symptoms of PCP, a definitive diagnosis is preferred, particularly in patients in the ICU. Many HIV-associated respiratory diseases have overlapping or nonspecific presentations, which makes it difficult for even experienced clinicians to diagnose empirically. Definitive diagnosis allows for the timely administration of appropriate antibiotics and avoids exposure to unnecessary medications. We are currently unable to culture Pneumocystis, and thus, the diagnosis relies on visualization of the organism in a respiratory sample from a patient with a compatible clinical presentation.
PCP can be diagnosed either through examination of induced sputum or from samples obtained at bronchoscopy. Spontaneous sputum is generally not acceptable for diagnosis of PCP (48). Rarely, open lung biopsy is used to provide a diagnosis. Induced sputum has a sensitivity ranging from 56% to over 80%, but these numbers were generated by centers experienced in the technique (49,50,51,52,53). The usefulness of this test is often limited because many hospitals lack experience in examining induced sputum, and a negative sputum induction should be followed by a bronchoscopy. A recent study reported that serial sputum samples can improve PCP diagnosis (7). In the ICU, the technique is usually not used because patients are generally not able to tolerate the procedure or are intubated.
Bronchoscopy with BAL should be obtained when sputum induction is negative or cannot be obtained. For patients with HIV infection, BAL has a sensitivity of over 90% for diagnosis of PCP and should be performed as early as possible in undiagnosed patients (54). Transbronchial biopsy does not add significantly to the yield for PCP in an HIV-infected individual and is technically challenging in an intubated patient; however, it may be useful in diagnosing other pulmonary infections that are also in the differential (55). It is reasonable to perform transbronchial biopsy as part of the initial procedure when the probability of PCP is low or as a follow-up test when the initial BAL is nondiagnostic.
Traditional staining methods for PCP include Gomori methenamine silver, toluidine blue O stain, or a modified Wright-Giemsa stain. Immunofluorescent antibody staining can also be used to examine induced sputum or BAL and has a high sensitivity (56,57). Newer methods based on the molecular technique of polymerase chain reaction (PCR) are currently under investigation. A recent study compared PCR of BAL and sputum with traditional methods and found 100% sensitivity for BAL and 85% sensitivity for sputum, with a specificity of 90% to 100% for both (58). Because PCR is quite sensitive, its use might obviate the need to obtain invasive samples. For example, a study of quantitative touch down PCR of oral washes found that the technique had a sensitivity of 88% and a specificity of 85% (59). When a cutoff value was applied to the Pneumocystis copy number, specificity improved to 100%. PCR-based diagnosis is not yet widely available for PCP.
Treatment and Corticosteroids
The duration of PCP treatment is 21 days. First-line therapy for moderate to severe PCP is intravenous trimethoprim-sulfamethoxazole (TMP-SMX) (Table 116.2). TMP-SMX is curative in 60% to 86% of patients (60,61). The dosage of TMP-SMX is 15 to 20 mg/kg of trimethoprim and 75 to 100 mg/kg of sulfamethoxazole daily, divided every 6 to 8 hours. TMP-SMX is associated with a high rate of adverse reactions, particularly in those with HIV infection. Approximately one fourth to one half of patients will develop therapy-limiting toxicity (41,60,62,63,64). Adverse reactions to TMP-SMX include nausea, integumentary rash, elevation of transaminases, hyponatremia, hyperkalemia, renal insufficiency, and bone marrow suppression.
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Table 116.2 Summary of treatment regimens for PCP in the ICU in decreasing order of preference |
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Intravenous pentamidine isethionate is the preferred alternative treatment for patients who cannot tolerate TMP-SMX or have failed treatment. Patients should receive 3 to 4 mg/kg/day of pentamidine. Some studies have found that the efficacy of pentamidine is similar to TMP-SMX, but others have reported a lower survival rate with pentamidine (61% vs. 86% for TMP-SMX) (60,61,65). Pentamidine has several serious adverse effects that can limit therapy and may be seen in as many as 50% of patients. Toxicity from pentamidine includes nausea, hypotension, bone marrow suppression, hepatic transaminitis, and nephrotoxicity. Glucose levels should be monitored in patients receiving pentamidine because it is toxic to pancreatic islet cells and can result in initial hypoglycemia from a surge of insulin release, followed by hyperglycemia from inadequate insulin. Some patients can even progress to chronic diabetes mellitus. Pancreatitis also occurs with pentamidine and may be fatal (66,67). Other side effects that have been reported include myoglobinuria, hyperkalemia, and increases in creatinine kinase. Pentamidine also has cardiac effects with bradycardia, prolonged Q-T intervals, and ventricular arrhythmias (68,69).
When TMP-SMX and pentamidine are either ineffective or toxic, it is possible to use clindamycin and primaquine as another salvage regimen option, but this use may be limited in the ICU because primaquine is administered orally and its absorption may be impaired. Clindamycin should be dosed 600 to 900 mg every 6 to 8 hours intravenously, with primaquine given 15 to 30 mg orally daily. Patients should be tested for G6PD deficiency before starting primaquine. Side effects include rash, diarrhea, and methemoglobinemia.
Adjunctive corticosteroids have been shown to decrease mortality in those patients with moderate to severe PCP (26,27,70,71). A recent meta-analysis of all randomized trials of corticosteroids found that the administration of corticosteroids was associated with a risk ratio of 0.56 for mortality and 0.38 for requiring mechanical ventilation (72,73). Patients with a room air arterial oxygen pressure less than 70 mm Hg or with an alveolar-arterial gradient greater than 35 mm Hg should receive corticosteroids. Corticosteroid therapy should be started within 24 to 72 hours of initiation of PCP treatment, whether the diagnosis is confirmed or only suspected. Corticosteroids act to reduce the inflammatory response seen during the first few days of treatment, thereby preventing respiratory deterioration. The recommended regimen is 40 mg of oral prednisone given twice daily for 5 days, then 40 mg once daily for 5 days, and 20 mg daily for 11 days. If patients are unable to tolerate oral medications, intravenous methylprednisolone or dexamethasone can be substituted.
Treatment Failure
Due to the increased inflammatory response during the initial phase of treatment, clinical deterioration can frequently be seen in the first 3 to 5 days of PCP treatment. Patients may experience worsening hypoxemia and respiratory distress, and radiographic infiltrates may progress. This worsening is likely due to an inflammatory response to dead or dying organisms that results in increased capillary permeability and formation of pulmonary edema. Assessment of treatment failure is challenging given this potential for initial worsening combined with the inability to culture Pneumocystis or determine antibiotic sensitivities. In general, treatment should be continued for at least 5 to 10 days before diagnosing treatment failure and switching to another agent. It is important to remember that other diagnoses present at baseline or that have developed since admission can explain the patient's lack of improvement, and these diagnoses must be excluded before concluding that treatment failure is solely to blame. Other diagnoses to consider include nosocomial, community-acquired, or other opportunistic pneumonia, and cardiogenic or noncardiogenic pulmonary edema. Patients who worsen or fail to improve while receiving PCP treatment should undergo diagnostic procedures such as chest CT, sputum cultures, or echocardiography as clinically indicated. Repeat bronchoscopy is useful to identify pathogens other than PCP but is not useful to evaluate treatment failure because Pneumocystis can persist in the BAL, even in patients who are successfully treated (74).
It is unknown if treatment failure is more likely in patients with previous exposure to anti-Pneumocystis prophylaxis. Pneumocystis develops mutations at the dihydropteroate synthase (DHPS) locus with exposure to sulfa- or sulfone-containing medications such as TMP-SMX and dapsone (75,76,77). In other micro-organisms, mutations at this locus have been shown to produce resistance to TMP-SMX, but the evidence for clinically important resistance in Pneumocystis is not clear-cut. Some authors have found an increased mortality and rate of treatment failure in patients with DHPS mutations (78,79,80,81), but others have not observed this association (76,82). In general, most patients with previous exposure to TMP-SMX or dapsone respond to treatment with TMP-SMX, and it should still be regarded as first-line therapy for these patients.
Ventilatory Support
Because the physiology of PCP is very similar to that of ARDS, principles of ventilatory management should be the same. Barotrauma is of particular concern in ventilated patients with PCP, as the development of a pneumothorax heralds a poor prognosis. Although patients with PCP were not included in the ARDSnet study, these patients should probably be ventilated in a similar fashion—with tidal volumes of 6 mL/kg and levels of positive end-expiratory pressure as needed to maintain oxygenation according to the ARDSnet guidelines (83). Noninvasive positive pressure ventilation (NIPPV) with continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) may be useful in patients with PCP. One study found that use of noninvasive ventilation decreased the rate of intubation, lowered the number of pneumothoraces, and improved survival (84). NIPPV may be tried as a first-line ventilation mode in patients with PCP who are awake, cooperative, and able to protect their airway.
Bacterial Pneumonia
Both the use of TMP-SMX for PCP prophylaxis and HAART have contributed to an overall decline in the numbers of cases of HIV-associated bacterial pneumonia (BP) (85,86,87,88). Although absolute numbers of cases of BP have declined since the introduction of HAART, in some series it now accounts for a greater percentage of ICU admissions since the number of PCP cases has also declined (6,11). Clinical risk factors for BP include injection drug use, cigarette smoking, older age, and lower CD4+ cell count, although BP can occur in patients with any CD4+ cell count (87,89,90,91). There are limited data regarding ICU mortality, but one study found that 83% of HIV-infected patients admitted to the ICU with BP survived (7). CD4+ cell count below 100 cells/µl, shock, and radiographic progression have been associated with mortality from BP in HIV-infected patients (92). Nosocomial pneumonia has also declined since the introduction of HAART but is still common in mechanically ventilated patients (88).
Clinical Presentation
Clinical presentation of BP in the HIV-infected patient is similar to that in the non–HIV-infected population. Patients typically present with an acute onset of fever, cough, shortness of breath, and purulent sputum. Chest radiographs frequently reveal lobar infiltrates that may progress to an ARDS-like picture in severe cases. The most common causes of BP in HIV include Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, and Staphylococcus aureus. Drug resistant S. pneumoniae and S. aureus are more common in HIV-infected patients (93,94,95). Atypical pneumonia with Mycoplasma pneumoniae is reported in approximately 20% to 30% of HIV-infected patients with community-acquired pneumonia (CAP) but is less commonly a cause of ICU admission (96). HIV-infected patients are more likely to be bacteremic, particularly those with Streptococcus pneumoniae infection (97).
Diagnosis and Treatment
Diagnosis and treatment for both CAP and hospital-acquired pneumonia should generally follow published guidelines, although these guidelines do not specifically address pneumonia in HIV-infected patients (98,99,100). Blood cultures should be obtained. Sputum should be sent for Gram stain and culture, and bronchoscopy should be considered. Treatment should include empiric coverage for the organisms above. Because of the higher incidence of pseudomonal and staphylococcal pneumonia in HIV-infected patients with severe pneumonia, it is important to initiate coverage for these organisms. As methicillin-resistant Staphylococcus aureus (MRSA) is common in HIV infection and is associated with decreased survival (88), empiric antibiotics effective against this pathogen are warranted pending results of cultures and antimicrobial sensitivities.
Other Respiratory Diseases
Other respiratory diseases that occur in HIV-infected ICU patients include Mycobacteria tuberculosis pneumonia; fungal pneumonias such as Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, and Aspergillus fumigatus; cytomegalovirus pneumonia, and Toxoplasma gondii pneumonitis. Malignancies such as Kaposi sarcoma and non-Hodgkin lymphoma can also lead to respiratory failure, but they are far less common than infections.
Immune Reconstitution Inflammatory Syndrome
The immune reconstitution inflammatory syndrome (IRIS) is a life-threatening syndrome occurring in HIV-infected patients who are started on HAART. In the days to months following initiation of HAART, patients experience a paradoxical worsening or new onset of infectious signs or symptoms. The syndrome results from an improvement in the immune system with an increased inflammatory response against infectious agents that can occur before the CD4+ cell count has risen (101). Immune reconstitution is most often seen in infection with Mycobacterium tuberculosis, cytomegalovirus (CMV), Pneumocystis, Mycobacterium avium complex, and endemic fungi (101,102,103,104,105,106,107). Manifestations of IRIS that can result in the need for ICU care include pneumonitis, meningitis, hepatitis, and pericarditis.
Respiratory failure secondary to IRIS is most common in tuberculosis and PCP (105,108,109,110). Paradoxical worsening in these cases presents with fever, hypoxemia, and new or increased radiographic infiltrates. Care is supportive, and corticosteroids are generally advocated, particularly in cases of PCP. Antiretroviral regimens should be continued whenever possible. Because this syndrome can be difficult to distinguish from acute opportunistic infections or other causes of respiratory deterioration, it is imperative that other causes of respiratory failure are sought before assigning a diagnosis of IRIS.
Sepsis and Bacteremia
Sepsis is increasingly common among HIV-infected patients admitted to the ICU, and its mortality rate has been reported to be as high as 68% (9,20,111). In the HAART era, more deaths in the HIV population have been attributed to sepsis (112). Care of the HIV-infected patient with sepsis should follow current guidelines (113). Broad-spectrum antibiotics should be based on the patient's CD4+ cell count, the presumed source, and previous use of prophylactic antibiotics that might predispose to resistant bacteria. Clinicians should consider empiric coverage for mycobacterial diseases and endemic fungi as suggested by the patient's presentation. The use of corticosteroids or recombinant-activated protein C has not been extensively studied in the HIV-infected population. Because HIV-infected patients have a high incidence of adrenal insufficiency, it is prudent to evaluate all septic HIV-infected patients and initiate therapy if cortisol levels do not increase appropriately with stimulation. Use of activated protein C can be difficult in this population because it should not be administered to patients with platelet counts below 30,000 cells/µL or to those with a history of a central nervous system (CNS) lesion.
Neurologic Manifestations of Hiv
The spectrum of neurologic disorders requiring critical care for patients with HIV infection includes all the causes commonly seen in the non–HIV-infected population in addition to particular opportunistic infections, neoplasms, and sequelae of HIV. In one series, neurologic diagnoses accounted for 12% of ICU admissions and had a 75% survival in the HAART era (6). An earlier series found that as many as 80% of these conditions required mechanical ventilation (114). A recent study of neurologic causes of ICU admission found that CNS toxoplasmosis and progressive multifocal leukoencephalopathy (PML) had decreased, but the incidence of ischemic stroke, hemorrhagic stroke, and primary CNS lymphoma had increased (115).
CNS toxoplasmosis is one of the most frequent CNS infections seen, although the number of cases has fallen dramatically with the introduction of HAART. Patients typically present with fever, headache, focal neurologic deficits, and a decreased level of consciousness; seizures can also occur. CT scan reveals characteristic ring-enhancing lesions (Fig. 116.2). Similar findings can also be seen with CNS lymphoma. Treatment for CNS toxoplasmosis is pyrimethamine given as a 200-mg loading dose, followed by 50 to 75 mg orally every 24 hours, with sulfadiazine at a dose of 1 to 1.5 g every 6 hours orally. Patients should also receive 10 to 20 mg of folic acid daily while receiving pyrimethamine. Other CNS infections that are seen in HIV infection include bacterial and Cryptococcus neoformans meningitis. Diagnosis of C. neoformans is confirmed by visualization of encapsulated yeast on cerebrospinal fluid (CSF), a positive CSF culture, or a positive CSF cryptococcal antigen. Treatment should be initiated with amphotericin B (0.7 mg/kg/day intravenously) and flucytosine (100 mg/kg/day orally, divided into four doses). Repeated lumbar puncture is often required to normalize CSF pressure. Other CSF infections that occur in HIV include PML, which is a progressive demyelinating disease, CMV, and herpes simplex virus. Any of these diseases can worsen and present with a neurologic immune reconstitution inflammatory syndrome in the setting of introduction of HAART (115).
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Figure 116.2. Contrast-enhanced head computed tomography scan from an AIDS patient with headache, word-finding difficulty, and several seizures showing a left frontoparietal ring-enhancing lesion (arrowhead) with mass effect on the lateral ventricle and a subtler focus of enhancement on the right at the gray-white junction (arrow). (Courtesy of Cheryl Jay, M.D., Associate Clinical Professor of Neurology, University of California, San Francisco.) |
Gastrointestinal Manifestations of Hiv
Gastrointestinal (GI) diseases, in particular liver diseases, have increased as a cause of death in HIV-infected patients (112). These diseases are either the primary cause or a complicating factor in the ICU admission of many HIV-infected patients. As in the non-ICU population, significant GI bleeding often results in ICU admission. Upper GI bleeding is more common than lower GI bleeding, and approximately half of the cases are HIV-related (116). Common HIV-associated diagnoses include infectious esophagitis (e.g., CMV) and ulcers, Kaposi sarcoma, and AIDS-associated lymphoma (116). In cases of lower GI bleeding, approximately 70% are a result of HIV infection (116). CMV colitis and idiopathic colon ulcers are most common, but Kaposi sarcoma, AIDS-associated lymphoma, and infections such as Mycobacterium avium complex may also contribute (117). Hemorrhoids and anal fissures can also result in significant bleeding in HIV-infected patients with thrombocytopenia (118). Care of the HIV-infected patient with a GI bleed is the same as for a non–HIV-infected patient and should include immediate resuscitation, source identification, reversal of coagulation defects, and achievement of hemostasis.
Coinfection with HIV and hepatitis C is increasingly common and complicates the management of both diseases. Mortality from hepatitis C has increased in recent years (119,120,121), and infection in HIV-infected individuals seems to be more severe with a higher mortality and risk of cirrhosis (122,123,124). There is also an increased risk of renal failure in hospitalized patients coinfected with HIV and hepatitis C (125). Hepatitis B is also common among HIV-infected patients.
Other GI conditions that are common in HIV-infected patients include peritonitis and bowel perforation. The most common cause of life-threatening abdominal pain is small bowel or colon peritonitis from CMV (126). Kaposi sarcoma, AIDS-associated lymphoma, and mycobacterial infection have also been associated with bowel perforation (117). Pancreatitis can also be seen, particularly with exposure to certain antiretroviral medications or pentamidine. AIDS cholangiopathy can result from various infectious and neoplastic processes and can be asymptomatic or present with fulminant biliary sepsis (117). In addition to the usual care of cholangitis with intravenous fluids and broad-spectrum antibiotics, endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy may be helpful in patients with common bile duct dilatation (126).
Other Hiv-Associated Conditions
Cardiac Disease
Since the introduction of HAART, there has been growing evidence that HIV-infected patients are developing premature atherosclerosis, and cardiovascular disease is now a primary cause of non–HIV-related deaths in these patients (112,127). Therefore, these patients may be more commonly admitted to the ICU with acute coronary syndromes.
The development of metabolic abnormalities that contribute to atherosclerosis has been associated with the use of nonnucleoside reverse transcriptase inhibitors (NNRTIs) and/or protease inhibitors (PIs). Elevated triglycerides, hypercholesterolemia, decreased high-density lipoproteins, glucose intolerance, and frank diabetes have all been associated with various antiretrovirals (128,129,130,131). There may also be direct endothelial effects of PIs or HIV itself that play a role in the development of vascular complications (132). Because of the higher rate of these metabolic abnormalities, combined with a high prevalence of cigarette smoking, it has been postulated that HIV-infected patients might have advanced cardiac and cerebrovascular disease, but several large-scale studies have had varying results (133,134,135). Even if the risk of cardiovascular events is elevated compared to non–HIV-infected patients, it is still low, particularly in comparison to the dramatic improvements in morbidity and mortality associated with HAART. There are few data on treatment or outcomes of cardiac disease specifically in the HIV-infected population, but treatment of acute coronary syndromes should be the same as in the non–HIV-infected population. A study of HIV-infected patients undergoing cardiac surgery found that these patients had favorable outcomes and should be referred for coronary artery bypass grafting when appropriate (136).
Renal Disease
HIV-infected patients are at risk of acute and chronic renal failure that can either lead to ICU admission or complicate care in the ICU. Renal function is abnormal in approximately 30% of HIV-infected subjects, and HIV-associated nephropathy is a common cause of end-stage renal disease (137). Renal dysfunction can occur from use of certain antiretroviral medications and other therapies such as pentamidine, TMP-SMX, and amphotericin B. HIV-infected patients who are coinfected with hepatitis C also have an increased risk of renal failure (125). HIV-associated nephropathy is another common cause of renal dysfunction and seems to improve with the administration of HAART (137). The diagnostic workup and treatment of renal dysfunction in HIV-infected patients is similar to that for the non–HIV-infected patient and should include renal ultrasound to rule out obstruction, examination of the urine, discontinuation of nephrotoxic medications, and renal biopsy if indicated. Dialysis should be offered to appropriate patients.
Metabolic Abnormalities
Metabolic abnormalities are common in the HIV-infected ICU patient. As described above, lipid and glucose abnormalities are often seen. Hyperglycemia secondary to drugs such as pentamidine also occurs in this population. It has been noted that hospitalized patients with HIV have high rates of hyponatremia (138,139,140). Causes of hyponatremia include hypovolemia, adrenal insufficiency, drugs, and the syndrome of inappropriate antidiuretic hormone (SIADH). A high incidence of adrenal abnormalities has been noted on autopsy of HIV-infected patients (141,142). Causes of adrenal pathology include infections such as CMV, tumors such as Kaposi sarcoma, and drugs such as ketoconazole and pentamidine. The clinical significance of the adrenal abnormalities is uncertain, but it seems that HIV-infected patients have a higher likelihood of adrenal dysfunction (25,143). Adrenal insufficiency can present with hyperkalemia, hyponatremia, and hypotension, and patients with these symptoms should be evaluated and treated appropriately. As with non–HIV-infected patients, adrenal insufficiency is likely common in sepsis.
Lactic acidosis is another metabolic abnormality that can occur in HIV-infected patients receiving HAART. This syndrome was first described in the 1990s and can occur with any nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) but is most commonly seen with didanosine and stavudine (144,145). Mitochondrial toxicity secondary to impaired synthesis of adenosine triphosphate (ATP)-generating enzymes is believed to be the cause of lactic acidosis (146). Patients particularly at risk of developing lactic acidosis from these drugs include those with a creatinine clearance less than 70 mL/minute and a nadir CD4+ cell count below 250 cells/µL (147). Although some patients may have only an asymptomatic lactic acidosis, others present with life-threatening acidemia. These patients also commonly complain of abdominal pain, nausea, and vomiting. Hepatic steatosis and transaminitis also occur, and patients can progress to respiratory failure and shock. In any patient presenting with these symptoms, an arterial lactate level should be checked and all antiretroviral medications discontinued if the level is greater than 5 mmol/L. Supportive care should be administered with bicarbonate therapy and hemodialysis if necessary. Based on anecdotal data, riboflavin, thiamine, and L-carnitine may reverse toxicity (148,149,150,151). Riboflavin is administered at a dose of 50 mg daily with 50 mg/kg of L-carnitine, and 100 mg of thiamine. Although the exact length of treatment is unknown, it should be continued at least until acidosis resolves.
Fever of Unknown Origin
Fever is common in all ICU patients. The differential for fever is broad in the HIV-infected patient and includes infections, neoplasms, medications, and collagen vascular diseases. Several studies have examined the etiology of fevers of unknown origin in those with HIV infection. Most studies have found that infectious causes are responsible for most prolonged fevers in the HIV-infected patient, with mycobacterial diseases diagnosed most commonly. PCP and bacterial infections are also seen (152,153,154,155). The most common neoplastic cause of prolonged fever is lymphoma. Patients receiving HAART are less likely to present with a fever of unknown origin than those not receiving HAART (156).
Recurrent fever in an HIV-infected ICU patient should also prompt evaluation of those conditions commonly seen in non–HIV-infected ICU patients. Common infectious causes of fever in the ICU include hospital-acquired pneumonia, catheter-related infections, sinusitis, and pseudomembranous colitis. Noninfectious causes include drug reactions (which are particularly common in those with HIV), pancreatitis, venous thromboembolism, acalculous cholecystitis, adrenal insufficiency, and thyroid storm. Diagnostic workup should include standard evaluation for infections such as blood, sputum, and urine cultures. Bronchoscopy with BAL should be performed in patients who demonstrate a new infiltrate on chest radiograph or have a worsening respiratory status. Testing should be performed for mycobacterial and fungal pathogens. Other testing should be performed as would be done in the non–HIV-infected population.
Antiretroviral Therapy in the Icu
Treatment Strategies
HIV-infected patients may be receiving antiretroviral therapy at the time of ICU admission or may have antiretroviral therapy initiated in the ICU. The use of antiretroviral therapy in critically ill patients presents distinct issues related to drug delivery, dosing, drug interactions, and antiretroviral-associated toxicities. The success of HAART in decreasing HIV-associated morbidity and mortality has raised questions regarding the ability of HAART to improve outcome in critically ill HIV-infected patients. It is unclear if the risks associated with HAART outweigh the potential benefits and if patients who are already receiving HAART should continue therapy in the ICU.
There are several factors related to using HAART in the ICU that are important to consider. HAART improves immune function. In chronic HIV infection, improving immune function with HAART significantly reduces the risk of opportunistic infections and neoplasms. This could contribute to reductions in morbidity and mortality in critically ill HIV-infected patients by decreasing the risk of subsequent HIV-associated diseases. HAART is also important in treating conditions such as PML that otherwise lack effective therapy. For these patients, HAART use may be necessary, even in the face of significant risks. For patients already receiving HAART, discontinuing therapy could result in the selection of drug-resistant virus that could limit future therapy. This is especially true if patients are receiving efavirenz or nevirapine, as these antiretroviral medications have longer half-lives than other antiretroviral medications. As a result, levels of these medications may persist as the levels of the other antiretroviral medications decrease, resulting in functional monotherapy.
HAART is also associated with several risks. Drug interactions and HAART-associated toxicities complicate management. In addition to issues regarding antiretroviral drug delivery and absorption, there are uncertainties surrounding dosing in acute and multiple organ system failures. These uncertainties could place patients at risk for subtherapeutic drug levels and drug resistance or, conversely, supratherapeutic levels and toxicity. Immune reconstitution inflammatory syndromes could result in significant clinical worsening of an already critical disease. The potential threat of this syndrome may make physicians reluctant to initiate HAART in the ICU.
There are no randomized clinical trials and no consensus guidelines to assist in decisions regarding HAART use in the ICU. Only a few retrospective studies address some of the clinical issues that clinicians face. Although decisions regarding HAART use in the ICU require a case-by-case basis review, Huang et al. (157) suggested the following framework (Fig. 116.3). Patients receiving HAART prior to ICU admission who have evidence of virologic suppression (plasma HIV RNA below the limit of detection) should continue HAART, if possible. These patients should have no contraindications to continuing HAART such as drug interactions or HAART-associated toxicities. Prompt placement of a feeding tube is especially critical in these patients, as lapses in therapy create the potential for subtherapeutic antiretroviral drug levels and the emergence of HIV drug resistance. In patients whose plasma HIV RNA is detectable despite HAART, the risks of continuing HAART may outweigh the benefits of this incomplete HIV viral suppression. However, consultation with an expert in HIV medicine should be obtained prior to any decision to continue, switch, or discontinue HAART.
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Figure 116.3. Treatment strategies for patients with HIV in the ICU. This algorithm provides a framework for making decisions regarding the use of antiretroviral therapy in the ICU. (Reproduced from Huang L, Quartin A, Jones D, et al. Intensive care of patients with HIV infection. N Engl J Med. 2006;355:179, with permission.) |
Patients not receiving HAART prior to ICU admission represent the largest proportion of HIV-infected patients admitted to the ICU (6,7,8,9). Two studies from the HAART era suggest that patients admitted with an AIDS-defining diagnosis, especially PCP, have the poorest prognosis and, thus, the greatest theoretical benefit from HAART (6,21). Although one study found that patients receiving or started on HAART during admission for PCP had decreased mortality (25% versus 63%), this study was retrospective and based on a limited number of patients.
Based on the limited available data, HAART initiation should be deferred in HIV-infected patients admitted to the ICU with a non–AIDS-associated condition (Fig. 116.3) (157). The immediate prognosis in these patients is generally better than for an AIDS-associated diagnosis, and the short-term outcome is most likely related to successful treatment of the underlying non-AIDS condition (6). As a result, the risks of HAART initiation in the ICU outweigh the short-term benefits of this therapy. If, however, patients remain in the ICU for a prolonged period, HAART (and opportunistic infection [OI] prophylaxis) should be considered if the patients have a CD4+ cell count less than 200 cells/µL since the risk of opportunistic infections is increased below this CD4+ count.
In contrast, HAART should be considered for HIV-infected patients admitted to the ICU with an AIDS-associated diagnosis. This is especially true for patients whose condition is worsening despite optimal ICU management and treatment for the AIDS-associated condition. In these individuals, the prognosis is dire, and aggressive measures are warranted. Patients who receive HAART should be followed for development of the immune reconstitution inflammatory syndrome, and consultation with an expert in HIV medicine should be obtained.
Drug Delivery, Dosing, and Interactions
All of the currently approved antiretroviral medications are dispensed orally, either as tablets or capsules, with the sole exception of enfuvirtide, a fusion inhibitor that is delivered subcutaneously (Table 116.3). Several antiretroviral medications are available in an oral solution, but only zidovudine has an intravenous formulation. If these medications are to be continued or initiated in the ICU, tablets and capsules can be crushed and reconstituted for delivery via feeding tube. As an additional consideration, the administration of many antiretroviral medications requires the interruption of enteral feedings that are usually delivered continuously, while other antiretroviral medications should be taken with food to minimize adverse effects.
Critical illness may complicate the absorption of antiretroviral medications. Decreased gastric motility (158,159), continuous feeding (160), nasogastric suctioning, and gastric alkalinization recommended for stress ulcer prophylaxis (113) may contribute to variations in the absorption of enterally administered drugs. H2-blockers and proton pump inhibitors, used for stress ulcer prophylaxis, are contraindicated with certain antiretroviral medications, necessitating the use of alternative prophylaxis agents or antiretroviral medications (Table 116.4) (161). Absorption of subcutaneously injected medications may also be altered (162,163). Furthermore, atypical drug volumes of distribution and compromise of elimination pathways due to acute organ failures may confound the achievement of appropriate drug levels (164).
The impact of acute and multiple organ system failures on the pharmacokinetics of antiretroviral medications, particularly when used in combination, have been largely unstudied. The presence of renal insufficiency or hepatic impairment will affect antiretroviral dosing. Renal insufficiency will reduce the clearance of all NRTIs except abacavir and will require dose adjustment of these NRTIs (Table 116.3). Patients with renal insufficiency cannot use most of the fixed-dose NRTI combinations. Instead, each antiretroviral medication must be used individually and dosed accordingly. Liver impairment will reduce the hepatic metabolism of many PIs and NNRTIs and will require dose adjustment of these medications (Table 116.3). Finally, as the patient's renal and hepatic functions change, the dose of these medications must be readjusted accordingly.
Antiretroviral medications, especially NNRTIs and ritonavir-boosted PI regimens, have several important drug interactions with other medications (Table 116.4). These interactions involve other HIV-associated medications, including those for opportunistic infection treatment or prevention, and common ICU medications, especially benzodiazepines. Midazolam, a benzodiazepine of choice in the ICU, should be avoided in nonventilated patients who are receiving NNRTIs or PIs, as benzodiazepine drug levels may be markedly increased (161). For mechanically ventilated patients, any resulting increased sedation may be a relative rather than an absolute contraindication. However, excess sedation is a significant factor in patients weaning from a ventilator and nearing extubation. Other drug–drug interactions may require close monitoring, dose adjustment (increase or decrease), or avoidance of a specific antiretroviral medication and/or the other drug.
Drug Toxicity
In general, the newer antiretroviral medications possess better safety profiles compared to their predecessors. Nevertheless, several antiretroviral medications are associated with potentially life-threatening and serious adverse effects (Table 116.5). Abacavir is associated with a hypersensitivity syndrome that, in rare cases, can lead to death if the patient is rechallenged. The rash associated with nevirapine can be severe, presenting with systemic symptoms and, in rare cases, progressing to Stevens-Johnson syndrome and toxic epidermal necrosis. Efavirenz is associated with mental status alterations that may be attributed erroneously to analgesics, sedatives, or the sleep-disrupted schedule in the ICU. These complications may be difficult to recognize as secondary to antiretroviral therapy. If toxicities to antiretroviral agents are suspected, the offending agent should be discontinued promptly. Since antiretroviral drug resistance can develop within days of a partially suppressive regimen, all antiretroviral medications should be discontinued or a replacement drug should be substituted for the suspected agent. Consultation with an expert in HIV medicine is recommended for patients with suspected antiretroviral-associated toxicities.
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Table 116.3 Antiretroviral Medication Formulations and Dosing |
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Table 116.4 Common ICU Medications and Potentially Serious Life-threatening Interactions with Antiretrovirals |
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Hiv Testing in the Icu
In the current era, up to 40% of patients are unaware of their HIV infection at the time of their ICU admission (6,7,8,9). For these patients, the first opportunity for HIV testing and diagnosis occurs in an ICU setting. Current guidelines recommend HIV testing whenever HIV infection is suspected (165). However, the prompt recognition of previously undiagnosed HIV infection and HIV testing and disclosure requirements present challenges to critical care physicians.
Most states have specific legislation regarding HIV testing, and significant differences exist between states, requiring health care providers to be aware of their state statutes and health codes. In general, HIV testing requires consent from the patient. If a patient is incapacitated, some states permit a surrogate to consent on the patient's behalf. HIV testing cannot be performed if a patient or their surrogate refuses HIV testing. As a result, physicians must weigh the risks and benefits of diagnostic procedures and empiric therapy without a confirmed diagnosis; these decisions may harm patients with and without HIV infection. For example, physicians may decide against pursuing bronchoscopy to diagnose PCP or initiating empiric PCP therapy that could be life-saving in an HIV-infected patient with PCP. Conversely, physicians may perform procedures or initiate therapies based on an incorrect assumption of underlying HIV infection, subjecting a patient without HIV to the resulting complications and toxicities.
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Table 116.5 Potentially Life-Threatening and Serious Adverse Effects of Antiretroviral Agents |
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In cases where HIV testing cannot be performed, well-intentioned physicians may wish to order plasma HIV RNA assays or CD4+ cell counts to infer HIV status. This practice is ill-advised and may be in violation of legal statutes in some states, which specifically prohibit plasma HIV RNA testing without the appropriate counseling. Although a normal CD4+ cell count argues strongly against the presence of an HIV-associated opportunistic infection such as PCP, low CD4+ counts characteristic of advanced HIV disease are often seen in critically ill patients without HIV (166,167,168).
Control of Hiv Infection in the Icu
Blood-borne Pathogen Precautions
Risks for occupational transmission of HIV depend on the type and severity of exposure. Potentially infectious fluids include blood, any visibly bloody body fluid, semen, vaginal secretions, and cerebrospinal, synovial, pleural, peritoneal, pericardial, and amniotic fluid. Transmission may occur via percutaneous injury or via contact with mucous membranes or nonintact skin with infectious material. The average risk for transmission of HIV following a percutaneous exposure to HIV-infected blood is estimated to be approximately 0.3% (169). Transmission after mucous membrane exposure is estimated to be approximately 0.09% (170).
Primary preventive measures should be used to decrease the risk of exposure to HIV, as well as other infections including hepatitis B and C. Health care workers should use universal precautions for handling blood and body fluids for all patients, regardless of known HIV status. These precautions include the routine use of personal protective equipment such as gloves, face protection, and gown, depending on the nature of the procedure, anticipated contact with blood or bodily fluids, and the potential for splashing or splattering of fluids (171). Additional components of a primary prevention strategy include work practice controls—for example, not recapping needles, announcing all sharps introduced onto or removed from the field, not leaving sharps on the field—and engineering controls—for example, self-retracting needles, needleless systems, and sharps disposal containers (172).
Management of Needle Sticks
In health care workers exposed to potentially infectious body fluids, secondary prevention measures should be used promptly. The first step in postexposure management is the immediate cleaning of the site of injury or skin exposure with soap and water (172). Mucous membranes should be flushed with copious amounts of water (173). Exposures should be reported promptly to the appropriate contact at each facility. If the HIV status of the source patient is unknown, evaluation of the risk factors and HIV testing following proper consent procedures should be performed.
In workers with a potential exposure to HIV, postexposure prophylaxis (PEP) should be offered urgently. Decisions of whether to initiate PEP when exposure occurs from a patient with unknown HIV status depend on the type and severity of exposure, prevalence of HIV in the community, and HIV risk factors of the patient. However, the decision to start prophylaxis will often need to be made prior to establishing the HIV status of the source patient. PEP should be begun within hours of exposure, as data suggest that postexposure prophylaxis is likely to be more effective if started shortly after exposure (170,172).
Selection of the PEP antiretroviral regimen depends on the efficacy of the antiretroviral agents and likelihood that the strain of HIV will be susceptible to different agents, as well as the pill burden, tolerability, and any comorbidities or use of concurrent medications in the health care worker. Basic two- or three-drug antiretroviral regimens are recommended by the Centers for Disease Control and Prevention (CDC), depending on the HIV status of the patient and the severity and type of exposure; specific recommendations are available from the CDC (170). Expert consultation should be considered early, particularly in cases with exposure to documented HIV drug resistance. In an earlier study, use of zidovudine following exposure in health care workers was associated with a decrease in the risk of transmission by an estimated 80% (174). No studies have specifically addressed the additional benefit of combination antiretroviral therapy following occupational exposure, but the risk of transmission is likely to be further decreased with multidrug regimens (170).
Substantial side effects are associated with PEP. A full 4-week course of treatment is recommended, although studies suggest that many are unable to finish a complete course (170). Side effects are reported in as many as 75% of persons on PEP (172). Balancing the risk of toxicity related to a three-drug compared to a two-drug regimen depends on the degree of risk associated with the exposure. Because of toxicity, PEP is not justified in exposures that have a negligible risk for transmission of HIV.
Health care workers with potential exposure to HIV should undergo serial HIV antibody testing. The CDC-recommended schedule is initial testing at the time of exposure, with repeat testing at 6 weeks, 12 weeks, and 6 months after exposure (170). Testing should be extended to 12 months in those with dual exposure to HIV and hepatitis C. Health care workers should also receive counseling at the time of exposure to discuss ways to decrease risk of exposures in the future, measures to decrease the risk of secondary transmission, and side effects of any treatments. Re-evaluation within 72 hours after exposure is warranted, particularly as additional information regarding the source patient may be available, and PEP may be discontinued if HIV testing of the source patient is negative.
Respiratory Isolation
As with HIV-uninfected patients, HIV-infected patients with suspected airborne-spread infections should be placed in respiratory isolation. Airborne precautions in the hospital setting consist of the use of personal protective equipment in the form of respirators and engineering controls such as the use of negative-pressure rooms (175). Diseases requiring airborne isolation precautions include tuberculosis, varicella (chickenpox and herpes zoster), measles, and the severe acute respiratory syndrome (SARS) (175). Because tuberculosis is common in the HIV-infected population and is often difficult to distinguish from other types of pneumonia, most HIV-infected patients with respiratory symptoms and chest radiographic abnormalities should be considered for respiratory isolation. The immune status of staff caring for the patient should also be considered, and limiting the number of staff exposed to the patient may be warranted. Patients with suspected airborne-transmitted diseases should wear a surgical mask during transport. Criteria for removing patients from respiratory isolation vary by disease. For example, patients with tuberculosis can be removed from respiratory isolation when the patient is on effective therapy, is clinically improving, and has three consecutive negative sputum smears for acid-fast bacilli on different days or tuberculosis has been ruled out.
Summary
In summary, the outcome for HIV-infected ICU patients has improved dramatically since the beginning of the AIDS epidemic. The spectrum of admitting diagnoses in the ICU has shifted to include more non–HIV-related conditions and diagnoses related to side effects of HAART. Because many patients are admitted to the ICU as their first manifestation of HIV, clinicians also need to consider a diagnosis of HIV in any patient with a compatible clinical history. Issues regarding continuing or starting HIV therapy are complex, and although HAART seems to have had some impact on the outcomes of critically ill HIV-infected patients, much remains to be discovered about its role in the ICU. Unfortunately, few data exist to guide clinicians in this difficult decision, and until future randomized, controlled studies examine this question, physicians must balance the risks and benefits for individual patients.
Pearls
· Intensive care survival of HIV-infected patients has improved over the course of the AIDS epidemic with survival rates that justify ICU care for most patients.
· Diagnoses such as bacterial pneumonia, sepsis, and non–AIDS-related conditions have increased in frequency since the introduction of highly active antiretroviral therapy (HAART).
· Definitive diagnosis is highly recommended in patients with HIV. Early bronchoscopy with bronchoalveolar lavage should be performed in patients with pneumonia who do not have an established microbiologic diagnosis.
· Despite decreasing numbers of cases of Pneumocystis pneumonia (PCP), PCP is still common in HIV-infected patients. It is associated with a high mortality, particularly in those patients with a pneumothorax while on mechanical ventilation. Many patients admitted with PCP are not aware of their HIV status.
· First-line treatment for PCP is intravenous trimethoprim-sulfamethoxazole, although many patients develop side effects. Corticosteroids should be given to those meeting oxygenation criteria.
· Immune reconstitution inflammatory syndrome can result in pneumonitis, meningitis, hepatitis, and pericarditis. Respiratory failure is most often from tuberculosis and PCP. The syndrome occurs after starting HAART and needs to be distinguished from acute opportunistic infections.
· Patients can develop fatal lactic acidosis as a result of antiretroviral medications. Treatment consists of drug discontinuation. Administration of riboflavin, thiamine, and l-carnitine might be helpful but is unproven.
· Coinfection with HIV and hepatitis C is increasingly common and can complicate ICU care.
· Administration of HAART in the ICU is challenging because of the multiple side effects and drug interactions, difficulty with administration of oral medications, and the possibility of inducing viral resistance; however, use of these medications may be beneficial in certain patients.
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