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Friday, January 13, 2012

HIV / AIDS intensive care

Author : Laurence Huang, M.D. Professor of Medicine University of California San Francisco Chief, HIV/AIDS Chest Clinic San Francisco General Hospital

2008-07-28

Introduction

Combination antiretroviral therapy has changed human immunodeficiency virus (HIV) infection and the acquired immune deficiency syndrome (AIDS) from a uniformly fatal disease to a chronic disease that cannot currently be cured but can successfully be treated with medications. The effectiveness of these medications and the promise of newer medications have created an optimistic long-term prognosis for persons with HIV/AIDS. This optimism may play a role in decisions regarding the use of intensive care and intensive care unit (ICU) management. Although the guiding principles of all ICU management pertain to critically ill persons with HIV/AIDS, antiretroviral therapy and unresolved questions regarding its use in the ICU add an additional level of complexity to already complicated patients. This article provides an overview of the spectrum of diseases in persons with HIV/AIDS that require intensive care, as well as predictors of outcome. The article focuses on some of the challenging issues associated with the intensive care of these individuals, including legal statutes concerning HIV testing and disclosure, the administration of antiretroviral medications, important potential drug-drug interactions with common ICU medications, and current controversies surrounding antiretroviral therapy use in the ICU.  
HIV electron micrograph. Source : CDC

Spectrum of diseases in the ICU: past, present, and future

Early in the HIV/AIDS epidemic, respiratory failure due to Pneumocystis pneumonia (PCP) accounted for up to 84% of ICU admissions for persons with HIV/AIDS. Experience treating persons with PCP and intensive care of these patients was limited and the mortality rates were extraordinarily high, ranging from 62% to 94%. Against the backdrop of AIDS, at the time an untreatable and fatal disease, physicians and patients alike questioned the appropriateness of intensive care for persons with HIV/AIDS, especially those with PCP. A majority of physicians surveyed during 1984-85 felt that mechanical ventilation (the use of a ventilator to mechanically assist or replace spontaneous breathing when patients cannot do so on their own) was rarely or never indicated for an AIDS patient with PCP and respiratory failure. Less than 20% of 188 patients with AIDS surveyed in an outpatient setting during 1985 stated that they would want intensive care in the event of both severe memory loss and PCP-associated respiratory failure.

The pessimism surrounding intensive care for persons with HIV/AIDS lessened during the late 1980s to mid 1990s because of groundbreaking, but incremental advances in HIV care. The first class of antiretroviral medication – nucleoside reverse transcriptase inhibitors – was developed and antiretroviral monotherapy produced short-term reductions in the incidence of AIDS and opportunistic infections. Prophylaxis regimens prevented new and recurrent opportunistic infections. The treatment and management of PCP and other opportunistic infections improved. Trimethoprim-sulfamethoxazole and pentamidine, the mainstays of PCP treatment, were joined by several new regimens as effective PCP therapies. Adjunctive corticosteroid treatment significantly decreased the rates of respiratory failure and mortality associated with PCP. These advances created a more optimistic sense regarding the overall care – and by extension the intensive care of persons with HIV/AIDS, setting the stage for the current era.

By 1996, a new class of antiretroviral medication - HIV protease inhibitors - combined with nucleoside reverse transcriptase inhibitors to usher in the present era in HIV medicine. AIDS incidence and mortality decreased dramatically in areas of the world with access to these medications; and hospital admissions for persons with HIV/AIDS declined in parallel. Although no national surveillance databases exist to track persons with HIV/AIDS receiving intensive care, studies from San Francisco and Paris indicate that ICU admissions also decreased after combination antiretroviral therapy was incorporated into clinical practice. At San Francisco General Hospital, the annual number of ICU admissions for persons with HIV/AIDS has decreased from 111 per year (1992-1995) to 88.5 per year (1996-1999) to 62 per year (2000-2004). Annual ICU admissions for persons with HIV/AIDS at Bichat-Claude Bernard University Hospital in Paris have decreased from 94.5 per year (1995-1996) to 79 per year (1998-2000).
Over the past decade, a new clinical spectrum of intensive care for persons with HIV/AIDS has emerged. Respiratory failure remains the most common ICU indication but the proportion of ICU admissions due to respiratory failure has declined. At Beth Israel Medical Center (New York), respiratory failure accounted for 22% of HIV-associated ICU admissions from January through June 2001 compared to 54% a decade earlier. PCP and other AIDS-associated illnesses are no longer the most common indication for ICU admission. At San Francisco General Hospital, PCP has decreased from 84% (1981-1985) to 20% (1992-1995) to 14% (2000-2004) of the ICU admissions for persons with HIV. At Bichat-Claude Bernard University Hospital, the proportion of persons with HIV/AIDS admitted to the ICU for AIDS-associated diseases decreased significantly from 58% (1995-1996) to 37% (1997-June 1999) (p<0.001). The declines in PCP and AIDS-associated illnesses have been partially offset by increases in persons with HIV/AIDS being admitted to the ICU with pulmonary, cardiac, gastrointestinal, renal, and metabolic illnesses, which may or may not be related to underlying HIV disease.Because there are now six distinct classes of antiretroviral medications that dramatically improve the prognosis for persons with HIV/AIDS – and because the future likely has an even greater promise – there will be an even greater clinical spectrum of intensive care for persons with HIV/AIDS. Increases in both cardiopulmonary diseases and malignancies are anticipated with an aging HIV population that is living longer due to the effectiveness of these medications. End stage liver disease secondary to viral hepatitis has emerged as a frequent cause of morbidity and mortality in the HIV population; these patients may increasingly require intensive care unless current therapies for hepatitis improve significantly. 
The overall improved prognosis of persons with HIV/AIDS also has led to more aggressive management of other medical conditions in persons with HIV infection, including coronary artery bypass as well as liver, renal, and heart transplantation at selected specialty centers. As these procedures become more widespread in persons with HIV infection, clinicians will face a new wave of challenges related to the intensive care of these complex patients.
Finally, without dramatic changes in health care access and the stigma associated with HIV disease, HIV-associated illnesses will remain a primary cause for ICU admission at institutions that serve vulnerable populations and at those institutions who care for HIV-infected émigrés from parts of the world where HIV/AIDS prevalence is high.

What are the most common conditions that require intensive care?

The general conditions that require intensive care in persons with HIV/AIDS are similar to those in the general population, but the specific causes for these conditions may differ.
Respiratory conditions. Since the beginning of the HIV/AIDS epidemic, respiratory failure has been the most common indication for ICU admission among persons with HIV/AIDS. However, the proportion of ICU admissions due to respiratory failure has declined and the underlying causes of respiratory failure have changed. Earlier in the HIV/AIDS epidemic, respiratory failure was often due to PCP or another HIV-associated pneumonia (infection of the lungs). Currently, PCP and other infectious pneumonias are less common and non-infections conditions (e.g., chronic obstructive pulmonary disease, COPD, lung cancer) appear to be more common. The decline in AIDS deaths and resulting increased survival, the high proportion of cigarette smoking in persons with HIV/AIDS, and emerging data that underlying HIV infection itself may be an independent risk factor for COPD and lung cancer are postulated explanations for these observations.
Sepsis. Sepsis (infection that has spread into the bloodstream) is increasingly common among persons with HIV/AIDS admitted to the ICU, and its mortality rate has been reported to be as high as 68%. Most often, bacterial pathogens are the cause of the sepsis. More deaths in persons with HIV/AIDS have been attributed to sepsis in the present era than in the earlier eras. The precise explanation for this observation is unclear but the increase in drug resistant bacteria (e.g., drug resistant Streptococcus pneumoniae [DRSP] and mythically-resistant Staphylococcus aureus [MRSA]) is a concern in persons with HIV/AIDS as well as in the general population.

Neurologic conditions. The spectrum of neurological conditions that require intensive care for persons with HIV/AIDS includes all the causes seen in the general population (e.g., stroke) in addition to HIV-associated opportunistic infections and neoplasms. The main HIV-associated neurological opportunistic infections include Cryptococcus neoformans meningitis (inflammation of the meninges, the protective membranes covering the central nervous system) and Toxoplasma gondii encephalitis (inflammation of the brain). Worldwide, neurological presentations of Mycobacterium tuberculosis (TB) are an important consideration. The main HIV-associated neurological neoplasm is primary central nervous system (CNS) lymphoma. In one study, neurologic diagnoses accounted for 12% of the ICU admissions and had a 75% survival rate in the combination antiretroviral therapy era. A study of neurological causes of ICU admission in the U.S. found that Cryptococcal meningitis, Toxoplasma encephalitis, and progressive multifocal leukoencephalopathy (PML) had decreased, but the incidence of ischemic stroke, hemorrhagic stroke, and primary CNS lymphoma had increased.

Cardiac conditions. The classic and modifiable risk factors for atherosclerotic cardiovascular disease include hypertension, diabetes, dyslipidemias (usually hyperlipidemia or elevated levels of lipids), and cigarette smoking. In general, the risk of these conditions and therefore the risk of acute coronary events (e.g., acute myocardial infarction, also known as an MI or, more commonly, a heart attack) increase as age increases. Thus, increases in atherosclerotic cardiovascular disease and acute coronary events in persons with HIV/AIDS may result from these individuals living longer and developing the conditions associated with increased risk for MI. However, antiretroviral therapy is also associated with a host of atherogenic complications, including dyslipidemias, insulin resistance, and diabetes. Several studies suggest that antiretroviral therapy may have contributed to the increasing rates of cardiovascular disease in persons with HIV/AIDS, although traditional risk factors also remain important factors. Persons with HIV/AIDS may also develop HIV-associated cardiomyopathy (disease of the heart muscle, which results in decreased cardiac function) or HIV-associated pulmonary arterial hypertension (high blood pressure in the pulmonary arteries, the blood vessels that carry blood from the heart to the lungs) that may require intensive care.
Gastrointestinal and liver conditions. Gastrointestinal (GI) bleeding may require intensive care if the bleeding is severe and if the person’s blood pressure is unstable. Often the causes of upper GI bleeding in persons with HIV/AIDS are similar to those found in the general population (e.g., peptic ulcer, duodenal ulcer). The causes of lower GI bleeding are also similar to those found in the general population (e.g., diverticular disease) but HIV-associated conditions such as cytomegalovirus (CMV) colitis are important considerations.
End stage liver disease secondary to viral hepatitis has emerged as a frequent cause of morbidity and mortality among persons with HIV/AIDS. Furthermore, several antiretroviral medications for HIV are also active against hepatitis B virus (HBV), so decisions about antiretroviral therapy are intertwined with those regarding hepatitis therapy. If antiretroviral therapy is initiated in a person with untreated HIV and HBV infections, clinicians can co-treat HBV by selecting two or more of these HBV-active medications as components of the person’s HIV regimen. Persons receiving concurrent HIV and HBV therapy who are admitted to the ICU should have these therapies continued if possible, as severe flares of the underlying hepatitis B have been reported after discontinuation of therapy.
Renal Disease. End stage renal disease (ESRD or kidney failure) secondary to HIV-associated nephropathy (a type of kidney disease known as HIVAN), hepatitis B or C co-infection, diabetes and/or hypertension is now a frequent cause of morbidity and mortality among persons with HIV/AIDS. Because HIV infection itself appears to be the cause of HIVAN and may contribute to other renal diseases (e.g., immune-complex glomerulonephritides), persons with HIV/AIDS and HIVAN should be treated with combination antiretroviral therapy, which may slow the progression of disease.

What are the predictors of outcome?

Mortality in the ICU is related to the reason for ICU admission. Thus, predictors of outcome depend on the specific reason for ICU admission.
The highest mortality rates reported for persons with HIV/AIDS who require intensive care are respiratory failure and sepsis. If respiratory failure is due to PCP, mortality remains nearly 50% and is increased if accompanied by PCP-associated pneumothorax (collapsed lung) where mortality is greater than 90%. Sepsis mortality rates from 50% to 68% have been reported. For persons with HIV/AIDS who require intensive care for other HIV-associated conditions, the reported mortality is generally lower, below 50%. Furthermore, persons with HIV/AIDS who are admitted to the ICU for a non-HIV-related condition may have better outcomes than those who are admitted for a condition related to underlying HIV. In a study from San Francisco, patients admitted with a non-AIDS-associated diagnosis had a significantly higher odds of surviving than patients admitted with an AIDS-associated condition (odds ratio [OR] 2.9, 95% confidence interval [CI] 1.5-5.8, p = 0.002). In a study from New York, ICU admission with an HIV- associated illness was independently associated with increased mortality (OR 4.2, 95% CI 2.0-9.0, p < 0.001).
Mortality in the ICU is also related to the severity of the acute illness. 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). 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 have a higher mortality. In general, the CD4 cell count and the plasma HIV RNA level are inaccurate predictors of ICU or hospital mortality. However, long-term mortality after ICU admission is related to the underlying severity of HIV disease. Compared to earlier eras, long-term survival following ICU discharge is improved in the current combination antiretroviral therapy era.

Does the intensive care management of persons with HIV/AIDS differ from that of persons without HIV/AIDS?

As a general rule, the cardinal principles of ICU management are the same in persons with and without underlying HIV/AIDS. The first principles involve the “ABCs”: A = secure an airway (often by endotracheal intubation, which involves placing a breathing tube into the trachea to provide a means of mechanical ventilation); B = ensure adequate breathing; C = ensure adequate circulation and delivery of oxygen to vital organs. There are, however, unique features of intensive care for persons with HIV infection that are important to understand.
HIV testing in the ICU
Persons with risk factors for HIV infection may be admitted to the ICU without a prior (or recent) HIV test. In many cases, knowledge of the person’s HIV status may influence the specific diagnoses being considered (since certain diagnoses only occur in persons who have HIV) and, therefore, in these situations an HIV test could provide valuable clinical information. In the current era, up to 40% of persons with underlying HIV are unaware of their HIV infection at the time of ICU admission.
Nevertheless, HIV testing and test disclosure requirements were originally established to protect persons with HIV. In the ICU, these requirements may present inadvertent legal barriers that discourage, or even prevent HIV testing when a patient cannot provide their own consent. Because of these barriers, the intensivist may be forced to defer HIV testing until the patient recovers. Each state and the District of Columbia have specific legislation regarding HIV testing; an up-to-date compendium of each state’s HIV testing laws is available at http://www.ucsf.edu/hivcntr/StateLaws/I

Antiretroviral therapy in the ICU


Currently, there are six distinct classes of antiretroviral medication: nucleoside reverse transcriptase inhibitors, protease inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, CCR5 antagonists, and integrase inhibitors. Once initiated, strict adherence to combination antiretroviral therapy is recommended. The benefits of adherence to antiretroviral therapy include maximal and continued suppression of HIV viral replication, decreased rates of drug resistance, and increased survival. However, the use of antiretroviral therapy in critically ill persons with HIV presents distinct issues related to drug delivery, absorption, dosing, drug-drug interactions, and antiretroviral-associated toxicities. Some issues are unique to critically ill persons with HIV; others pertain to all persons with HIV but are especially important in the ICU. As a result, it may be difficult or impossible to continue antiretroviral therapy in a critically ill patient with HIV.

Drug delivery. Frequently, critically ill patients are unable to take medications by mouth. As a result, these patients often receive important therapies intravenously, via an intravenous catheter. Delivery of antiretroviral therapy in a person who is unable to take medications by mouth is complicated since all of the currently approved antiretroviral medications are dispensed as capsules or tablets except for enfuvirtide (administered via subcutaneous injection). Several antiretroviral medications are available as an oral solution but only zidovudine has an intravenous formulation. For medications without an intravenous or oral solution, the capsules can be opened and the tablets can be crushed and re-constituted for delivery via a feeding tube (a tube placed into the stomach for delivery of oral medications and nutrition). However, it is unclear whether the levels of the antiretroviral medications that are achieved through this approach are sufficient to suppress HIV viral replication. In addition, extended release and enteric-coated formulations should never be crushed as this will destroy the enteric coating and result in decreased plasma levels of the antiretroviral medication.
Drug absorption. In order to inhibit HIV viral replication, antiretroviral medications must be sufficiently absorbed to achieve certain levels in the bloodstream. Critical illness may complicate the absorption of oral medications and several factors can contribute to variations in the absorption of antiretroviral medications. For example, some antiretroviral medications require the interruption of continuous enteral feeding (delivering liquid nutrients directly to the GI tract) for optimal absorption, while other antiretroviral medications should be taken with food to minimize adverse effects. In addition, H2-blockers and proton pump inhibitors, used for stress ulcer prevention, are contraindicated with certain antiretroviral medications.
Drug dosing. The dose of many antiretroviral medications must be adjusted in persons with kidney or liver impairment. Since critically ill patients often have either kidney or liver impairment and the degree of impairment can change rapidly (within hours), the correct dosing of antiretroviral medications can be challenging. Low levels of these medications may increase the risk of drug resistance while high levels may result in increased side effects and drug toxicity.
Drug-drug interactions and antiretroviral-associated toxicities. Many antiretroviral medications have important drug-drug interactions with other medications. These interactions involve other HIV-associated medications and common ICU medications. In some instances, the concurrent use of these medications is contraindicated and may result in life-threatening side effects or toxicities. In other cases, medications may be used concurrently but their use requires close monitoring. The Department of Health and Human Services “Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents” maintains up-to-date tables of important drug-drug interactions and drugs with overlapping toxicities to guide clinical care (http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf).

Should antiretroviral therapy be used in critically ill persons with HIV/AIDS?


There are no randomized clinical trials that address the question of whether to use antiretroviral therapy for clinically ill persons with HIV/AIDS; therefore,  there is no precise answer.. However, there are compelling arguments for and against using antiretroviral therapy in the ICU. The relative risks and benefits of using antiretroviral therapy in a critically ill individual should be weighed carefully.
Arguments for antiretroviral therapy in the ICU. Antiretroviral therapy improves immune function; with the therapy CD4 cell counts (cells that defend the body against HIV and opportunistic infections) rise, and plasma HIV RNA falls. Although the short-term impact of increasing the CD4 cell count and decreasing the plasma HIV RNA level on ICU mortality is unclear, improving immune function with antiretroviral therapy could be beneficial. In persons with HIV, improving their immune function with antiretroviral therapy reduces the risk of HIV-associated opportunistic infections and malignancies. This could contribute to reductions in additional HIV-associated complications that increase mortality in critically ill persons. The lower toxicity associated with the newer antiretroviral medications and combinations further strengthen the argument for their use in the ICU. For patients already receiving antiretroviral therapy, discontinuing therapy could result in the selection of drug-resistant virus.
Arguments against antiretroviral therapy in the ICU. The considerable issues related to drug delivery, absorption, dosing, drug-drug interactions, and antiretroviral-associated toxicities combine to indicate that the use of antiretroviral medications is associated with significant risks to patients who are already in a life-threatening condition and cannot afford additional complications. Immune reconstitution syndromes (see below) could result in clinical worsening of an already critical disease and the threat of this syndrome may make physicians reluctant to initiate antiretroviral therapy in the ICU.
Immune reconstitution syndrome (IRS), immune reconstitution inflammatory syndrome (IRIS)
The immune reconstitution syndrome (IRS), also referred to as the immune reconstitution inflammatory syndrome (IRIS), is a serious, potentially life-threatening syndrome that can develop in persons with HIV who start on combination antiretroviral therapy. The syndrome results from an antiretroviral therapy-mediated improvement in the person’s immune system that results in an increased inflammatory response against infections. The improved immune function can develop even before the CD4 cell count has risen. IRS has been described with virtually all HIV-associated opportunistic infections but appears to be most common in persons with Mycobacterium tuberculosis, Mycobacterium avium complex, cytomegalovirus (CMV), Pneumocystis, and endemic fungi. IRS can present in one of two ways. First, IRS can “unmask” a previously undiagnosed opportunistic infection. More commonly, IRS paradoxically worsens a known opportunistic infection occurring in persons who are started on combination antiretroviral therapy at the same time or soon after treatment for the opportunistic infection.
The presentation of IRS depends on the underlying opportunistic infection. Respiratory failure secondary to IRS is most common in tuberculosis and PCP. Paradoxical worsening in these cases presents with fevers, cough, dyspnea (shortness of breath), hypoxemia (low levels of oxygen), and new or worsened chest x-ray findings. Antiretroviral regimens should be continued in persons with IRS whenever possible. (IS THE IMPLICATION HERE THAT WHILE THERE IS QUESTION ABOUT INITIATING THE THERAPY, CONTINUATION MAKES SENSE? PLEASE CLARIFY.) Care is supportive (SPECIFIC MEANING HERE?), and corticosteroids can be used in severe presentations, particularly in cases of PCP. 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 IRS. Thus, the diagnosis of IRS is one of exclusion.

Conclusion

HIV/AIDS has been transformed from a uniformly fatal disease to a chronic disease that cannot currently be cured but can be successfully treated with antiretroviral medications. As a result, intensive care for persons with HIV/AIDS is appropriate for most patients. However, the intensive care of these patients is complex and questions regarding the use of antiretroviral therapy in the ICU remain unanswered. Although the future holds promise, continued advances in our understanding in this area are needed to obtain the greatest benefit for the most critically ill.  

More information

Web Resources
Department of Health and Human Services AIDS Info: http://aidsinfo.nih.gov/
Department of Health and Human Services AIDS Info (current Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents): http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
Department of Health and Human Services Centers for Disease Control and Prevention (HIV/AIDS): http://www.cdc.gov/hiv/
Department of Health and Human Services Centers for Disease Control and Prevention (Global HIV/AIDS): http://www.cdc.gov/nchstp/od/gap/default.html
The National Institutes of Health Office of AIDS Research (OAR): http://www.oar.nih.gov/
University of California San Francisco HIV InSite: http://hivinsite.ucsf.edu/
 
Books
Raphael Dolin, Henry Masur, and Michael Saag. AIDS Therapy. 3rd Edition.
 

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