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
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/
Books
Raphael Dolin, Henry Masur, and Michael Saag. AIDS Therapy. 3rd Edition.
References
Dickson
SJ, Batson S, Copas AJ, Edwards SG, Singer M, Miller RF. Survival of
HIV-infected patients in the intensive care unit in the era of highly
active antiretroviral therapy. Thorax 2007;62(11):964-8.
Halpern, SD. HIV testing without consent in critically ill patients. Jama 2005;294(6):734-737.
Huang L, Quartin A, Jones D, Havlir DV. Intensive care of patients with HIV infection. N Engl J Med 2006;355(2):173-81.
Morris,
A, Wachter, RM, Luce, J, Turner, J, and Huang, L. Improved survival
with highly active antiretroviral therapy in HIV-infected patients with
severe Pneumocystis carinii pneumonia. Aids 2003;17(1):73-80.
Morris
A, Masur H, Huang L. Current issues in critical care of the human
immunodeficiency virus-infected patient. Crit Care Med 2006;34(1):42-9.
Wachter RM, Luce JM, Hopewell PC. Critical care of patients with AIDS. JAMA 1992;267(4):541-7.