The potential anesthetic threats, challenges and intensive care considerations in patients with HIV infection.

Acquired immunodeficiency syndrome (AIDS) has become a pandemic with ever looming danger of its transmission in health professionals. The number of AIDS patients has increased tremendously over the last two decades, who present for surgical procedures as well as who get admitted in intensive care unit for their critical condition. As such anesthesiologists and intensivists are exposed to potential risk of disease transmission on a daily basis from such patients. The guidelines and protocols formulated in the western world regarding prevention of disease transmission cannot be applied uniformly in the developing nations, such as India due to various factors and limitations. As such there is a continuous need felt in this arena to prevent the catastrophic consequences of AIDS in our medical fraternity while treating such patients in operation theatres and critical care units. This study reviews the various pathophysiological aspects, anesthetic considerations, intensive care implications, and various areas where current knowledge about AIDS can be applied to prevent its potential transmission in high-risk clinical groups.

Acquired immunodeficiency syndrome (AIDS) was first described in 1981 in adults and the causative agent was first isolated in 1983.[12] According to the United Nations report on AIDS in 2007, about 33 million people were living with human immunodeficiency virus (HIV) and around 2.7 million were newly infected.[3] Developing nations like India has about 2.5 million people infected with the virus.[3] As a result this pandemic of AIDS has engulfed the entire globe in its grip.

The medical fraternity is at the highest risk among various professions as they are invariably and frequently exposed to established and undiagnosed cases of AIDS. Anesthesiologist’ services are frequently sought either for any elective/emergency surgery or during the care of critically ill patients in intensive care unit (ICU). Though in established cases of AIDS, precautions can be taken but many a time during emergency situations and mass casualties, large numbers of patients are encountered. The potential risk of HIV transmission during these circumstances increases manifold from undiagnosed and unsuspected positive HIV cases. These risks certainly increase during the performance of invasive procedures such as intubation and airway management, securing of peripheral and central vascular access, insertion of Ryle's tube and urinary catheter. The risk increases further if the approach during these procedures is a casual one.

Tremendous advancement in understanding and management of this disease over the last decade has brought about prolongation of life span of the infected people. This subset of population can come for various types of elective or emergency surgeries, so the attending anesthesiologist is faced with managing these patients keeping in mind of various implications of this disease on anesthesia. An estimated 20-25% of all HIV infected patients come for various surgeries at some point of their lives.[4]

Aetio-pathogenesis

The causative agent is HIV belonging to the family retroviridae and subfamily lentivirus and is a single stranded RNA virus.[56] Two subtypes have been described: HIV 1 and 2. The pathogenesis involves binding of viral envelope protein GP160 to the specific CD4 receptors found on T4 lymphocytes (T-helper cells) of immune system. This process also requires a co-receptor named chemokine co-receptor (CCR5). After binding, the virion fuses with the host cell membrane and gets internalized. The viral RNA is then transcribed to host DNA by the enzyme reverse transcriptase present within the virion. This pro DNA is then integrated to the host DNA by the enzyme integrase. The viral DNA can remain integrated to the host DNA in an inactive form for many years. Once activated, the pro viral DNA transcribes viral RNA and messenger RNA which later forms various viral proteins forming viral progeny. Inhibition of viral replication is usually targeted by the various anti-retroviral agents. With the progress of the disease, the T-helper immune cells become deficient both quantitatively as well as qualitatively, leading to the opportunistic infections and neoplasms.

Classification of the disease

WHO and Centre for Disease Control and Prevention (CDC) have classified HIV infection according to the clinical symptoms and severity of immune suppression as depicted in Table 1.[7]

Table 1

World health organization clinical staging of HIV/AIDS

Immunological classification

According to the World Health Organization, established HIV infections can be classified based on the CD4 cell counts which suggests the severity of immunological compromise and also can be used to know the effectiveness of anti-retroviral therapy. The classification is depicted in Table 2.

Table 2

WHO immunological classification of established HIV-infection

Pre-operative Anesthetic Considerations

History and systemic examination

It has been observed and reported as well that during history taking only 20% of the physicians seek drug abuse history and much lesser than that enquire about the possibility of HIV infection.[8] Various systems may be involved due to direct consequence of opportunistic infections or neoplasms or may be due to other causes such as side-effects of anti-retro viral medications. Therefore, a detailed history encompassing physiological functioning of the individual organ system should be elicited.

Respiratory system

Both the upper as well as lower respiratory tract may be involved due to opportunistic infections or neoplasms, e.g., Kaposi's sarcoma. Bronchitis, sinusitis, pneumonia caused by encapsulated bacteria like Haemophilus influenzae, Streptococcus pneumonia, etc., have been seen as well as infection with Mycobacterium tuberculosis can develop early in the course of disease. Atypical mycobacterium and fungal infections are also common in these patients especially with low CD4 T-cell counts. Pneumocystis carinii opportunistic pneumonia has been found in most of the patients and may be the earliest indication of the disease.

Cardiovascular system

The cardiovascular system may be involved due to a primary HIV infection or due to the side-effects of anti-retroviral therapy. Pericardial effusion may arise due to infection itself, due to opportunistic infection or due to neoplasms. Dilated cardiomyopathy, known as HIV-associated cardiomyopathy, have been described as a late complication due to primary or secondary opportunistic infections or due to side-effects of anti-retroviral drugs like reverse transcriptase inhibitors, which causes mitochondrial toxicity. Acute coronary syndrome has been found in patients taking protease inhibitors more so in patients with pre-existing cardiovascular disease. Various auto-immune vasculitis like poly arteritis nodosa, Henoch-Schonlein purpura, Takayasu's arteritis and Kawasaki-like syndrome have been found in these patients. Recently, pulmonary arterial hypertension associated with HIV infection has also been described.[9]

Nervous system

Neurological abnormalities may develop in 90% of patients with HIV infection. Almost all the structures in nervous system may be involved, e.g., meninges, brain, spinal cord, peripheral nerves and muscles.[10] These include: Opportunistic infections, e.g., Cryptococcus, toxoplasma, aspergillus, candida, etc.

Aseptic meningitis

Subacute encephalitis

Herpes simplex encephalitis

Multifocal leukoencephalopathy

Autonomic neuropathy

HIV-related dementia and neurocognitive impairment.

Hematologic system

Various hematologic abnormalities associated with HIV infection includes:[10]

Thrombocytopenia

Anemia

Neutropenia

Coagulation abnormalities.

These may be a result of direct HIV infection, secondary opportunistic infections or toxic effects of anti-retroviral drugs.[11] Hematologic malignancies have also been described.

Renal system

Involvement of renal system may be due to nephrotoxic effects of anti-retroviral drugs causing acute renal failure or due to chronic effects of HIV infection leading to end stage renal disease. Anesthetic technique has to be modified in these patients with renal involvement in accordance with the severity of the disease.[1112]

Gastrointestinal system

Involvement of oral cavity with lesions due to candida or infiltrative neoplasms can lead to dysphagia and odynophagia. These lesions can easily bleed during instrumentation of upper gastrointestinal tract as in Ryle's tube insertion or direct laryngoscopy. Chronic diarrhea due to infection with cytomegalovirus, cryptosporidium or other bacteria can cause severe fluid and electrolyte imbalances and should be evaluated pre-operatively.

Endocrine system and metabolism

Lipodystrophy and metabolic syndrome involving elevated plasma triglycerides, glucose and cholesterol have been found due to side-effects of anti-retroviral therapy. Other abnormalities may include:

Hypercortisolemia

Adrenal insufficiency

Syndrome of inappropriate secretion of anti-diuretic hormone (SIADH)

Hypo- or hyperthyroidism

Lactic acidosis due to side-effects of anti-retroviral drugs, e.g., nucleoside/nucleotide analogues.

Laboratory Profile and Investigations

A thorough pre-anesthetic evaluation should be supplemented with laboratory data in all HIV infected patients to know the severity of disease, organ systems involved and presence of other co-morbid illnesses which may have implications on anesthetic technique. A complete evaluation of anti-retroviral drugs should be made pre-operatively.[11] Laboratory investigations should include:

Complete blood count with coagulation parameters, renal and hepatic function tests.

Electrocardiogram (ECG) and Echocardiogram if ECG shows abnormality.

Pulmonary function tests and arterial blood gas analysis to know severity of pulmonary system involvement.

Chest X-ray if indicated.

Advanced imaging modalities, e.g., CT scan, MRI, etc., to be done if clinical condition warrants.

The overall risk of anesthesia and surgery in HIV infected patients is not documented but no elective surgery should be deferred on basis of HIV positivity alone.[13] The type of anesthetic technique used in HIV infected patients depends upon the type of surgery, severity of HIV infection and presence of co-morbid diseases. General anesthesia can safely be used in these patients but drug interactions and systems involved and their implications should be kept in mind. Drugs like etomidate, atracurium, remifentanyl, and desflurane can be safely used as their metabolism is independent of cytochrome 450 enzyme.

Regional anesthesia can also be considered in less advanced disease with no neurological deficits or coagulation abnormalities. Central neuraxial blockade have been studied in obstetric anesthesia with no adverse effects provided no neurological deficits exist pre-operatively.[14-16]

Anti-retroviral therapy

Combination therapy known as highly active anti-retroviral therapy (HAART), have undergone tremendous advancement in recent years. The drugs are classified according to the mechanism of inhibition of viral replication as shown in Table 3.[10]

Table 3

Classification of anti-retroviral drugs with side-effects

Adverse drug effects

The side-effects associated with anti-retroviral drugs can be summarized as:[12]

Mitochondrial dysfunction: Lactic acidosis, hepatotoxicity, pancreatitis, peripheral neuropathy.

Metabolic: Lipodystrophy, hyperglycemia, body habitus changes, insulin resistance, osteoporosis.

Bone marrow suppression: Pancytopenia.

Allergi creactions: Skin rashes and hypersensitivity reactions.

Drug interactions

Interaction of anti-retroviral drugs with anesthetic drugs and other agents are very important as these patients usually are on multiple drugs.[11] Pharmacodynamic interactions may be avoided by proper selection of anesthetic agents that have minimal effects on hepatic or renal systems. NRTI's have been implicated in causing lactic acidosis and hence long term propofol infusions should be avoided in such patients.

Pharmacokinetic interactions involves induction or inhibition of hepatic enzymes particularly CYP4503A4 enzyme. The various group of anesthetic drugs affected are:

Opioids: Ritonavir (PI) both induces and inhibits hepatic enzyme thus enhancing the effects of fentanyl by reducing the clearance and by increasing the active metabolites

Benzodiazepines: Saquinavir (PI) inhibits midazolam metabolism

Calcium channel blockers: Enzyme inhibition can enhance their hypotensive effect

Neuromuscular blockers: Prolonged effects of muscle relaxants have been observed

Local anesthetics: Plasma levels of lignocaine may be increased due to enzyme inhibition.

Pre-operative anti-retroviral therapy

It is recommended to continue anti-retroviral therapy during pre-operative period to reduce drug resistance as long as it is compatible with the surgery. Only few anti-retroviral drugs, e.g., zidovudine, are available as parenteral preparations.

Anesthetic implications in obstetrical patients with HIV infection

Pregnancy in the setting of HIV infection has been the most debated topic among women of child bearing age and extensive research is being carried out throughout the globe. Anesthesiologists are also encountering increasing number of parturients some of them may be established cases while other gets diagnosed for the first time in the hospital setting.[4] As in other patients of HIV infection, patients’ disease status and current treatment should be reviewed carefully. The minimum necessary investigations required in these cases include hemoglobin, blood count, coagulation profile, liver function tests, renal panel, ECG, roentgenogram and echocardiography.

Choice of anesthetic technique

There had been concerns of immune suppression with general anesthesia but nothing conclusive has been established till date.[1718] However, the risk increases with administration of GA due to underlying pulmonary and cardiac pathology. Regional anesthesia had also been a subject of controversy due to claims of possible central nervous system involvement.[1920] It has been now clearly established that neuraxial anesthesia can be administered safely in patients with HIV infection.[2122] One of the chief concerns with this technique is the failure to treat the complications associated with post-dural puncture headache.[23]

The responsibility of anesthesiologist lies not solely in caring for the mother only but he has to take care of the neonate as well. Therefore, a judicious use of anesthetic drugs is warranted so as not to affect the neonatal apgar scores. The risk of transmission of HIV from mother to fetus is around 25% which can be reduced to 2% by combination of anti-retroviral therapy and elective caesarean section.[24-27] There is very little literary evidence to suggest that HIV increases complications of pregnancy or pregnancy alters the HIV disease progression in a parturient.[15] The marked reduction in incidence of disease transmission should not be the sole criterion for subjecting the parturients to elective caesarean section (CS) as maternal mortality and morbidity increases with operative delivery as compared to normal vaginal delivery.[28] However, American college of obstetrics and gynecology (ACOG) has stated that an elective CS should be offered to every HIV infected parturient to reduce the risk of vertical transmission.

Challenges in critically ill patients with HIV infection

The HIV infected patients may require intensive care for variety of reasons which may be due to complications arising out of primary infection or may be due to other surgical or medical reasons unrelated to HIV infection. With the advancement in anti-retroviral therapy, the mortality in HIV infected patients requiring intensive care have been reduced from 70% in 1980s to 30-40% in 2002.[29]

Major causes necessitating ICU admission

Respiratory

The most common reason for ICU admission in HIV infected patients is acute respiratory failure and Pneumocystis carinii pneumonia (PCP) constitutes about 25-50% of these cases.[29] There has been an improvement in survival rates in PCP related acute respiratory failure from 0-13% in 1980s to about 30-45% in 1990s, which may be attributed to the advancement in anti-retroviral therapy, increased use of PCP prophylaxis and adjunctive corticosteroid treatment in moderate to severe PCP. Patients usually presents with fever, dry cough and shortness of breath followed by oxygen desaturation on exertion severe PCP manifests on chest X-ray as diffuse bilateral granular opacities with development of air containing pneumatoceles, predisposing to pneumothorax. Bronchoalveolar lavage cytology is the gold standard for diagnosing PCP. The important differential diagnoses involve disseminated infection with histoplasma, coccidiomyces and invasive aspergillusfumigatus infection. About 20% of PCP infections are complicated with concomitant bacterial infection. The need for mechanical ventilation and presence of pneumothorax are considered as poor prognostic indicators in patients with PCP infection.[30]

Therapy with high dose trimethoprim-sulfamethoxazole combination is the first line treatment but is often complicated by rash, neutropenia and fever. Pentamidine and clindamycin comes as second line of treatment whereas primaquine and combination of dapsone with trimethoprim is reserved for those intolerant to first and second line of treatment. High dose corticosteroids within 24-72 hours of PCP treatment initiation can be considered in hypoxemic patients as these have shown to reduce morbidity and mortality.[31]

The other causes of acute respiratory failure in HIV infected patients are bacterial pneumonias caused by Pseudomonas, Staphylococcus aureus, etc., which usually require antibacterial treatment. HIV-associated lymphocytic interstitial pneumonitis and bronchiolitis obliterans organizing pneumonia (BOOP) are some rare pathology which may be seen in these patients.

Opportunistic mycobacterium infection is also frequent in HIV positive patients and is usually seen in conjunction with extra-pulmonary manifestations. The Mycobacterium avium complex (MAC) is also common in developed countries and is seen in those with CD4 counts less than 50/μl.

Neurological

The other common reason for intensive care admission in these patients may be neurological pathologies comprising up to 27% of admissions.[32] Cerebral toxoplasmosis is common in these patients and usually presents with focal neurological signs, fever, seizures and depressed consciousness. The diagnosis can be made by serum antibody testing and brain biopsy might be needed to differentiate it from other similar pathologies (cerebral abscess, tuberculoma, neurosyphilis and progressive multifocal leukoencephalopathy). The treatment includes sulfadiazine and pyrimethamine with high incidence of adverse drug reactions.

Another common infection seen in HIV-positive patients is cryptococcosis of central nervous system (CNS). It presents with non-specific symptoms of fever, headache and vomiting and the diagnosis is confirmed by demonstration of Cryptococci in cerebrospinal fluid on India ink staining. The treatment is usually with liposomal amphotericin B and flucytosine.

Other common CNS pathologies seen in these patients are non-Hodgkin's lymphoma, progressive leukoencephalopathy and HIV encephalopathy. Glasgow coma scale of less than 7 or signs of brainstem involvement at the time of intensive care admission are considered as independent predictors of mortality.[33]

Gastrointestinal

Bleeding from gastrointestinal tract often due to ulcerations, Kaposi's sarcoma, lymphoma, gastric or duodenal ulcers, varietal bleeding, etc., may result in intensive care admissions. Bowel perforation secondary to cytomegalovirus enteritis, lymphomas, cholangiopathy and pancreatitis are other possible causes of intensive care admissions in these patients.

Sepsis

Severe sepsis accounts for approximately 15% of diagnoses in HIV-positive patients admitted to ICU with an increased mortality as compared to those without HIV/AIDS.[34] Patients should undergo aggressive management with appropriate antibiotics as mortality in these patients is high.

The introduction to highly active anti-retroviral therapy (HAART), classification, mechanism of action of various drugs and common adverse effects has already been dealt before. An important adverse effect of HAART especially seen in ICU patients known as immune reconstitution inflammatory syndrome needs to be mentioned here. It is a life threatening adverse reaction seen days to weeks after initiation of HAART and usually presents as paradoxical worsening of previous infection which is either partially treated or recently treated with concomitant worsening hypoxemia and an increase in chest infiltrates and adrenomegalies.[35] It is thought to result from an exuberant inflammatory response in presence of pathogens, e.g. M. avium complex.[36]

Mortality predictors in IC

The predictors of poor prognosis or higher mortality in these patients admitted in intensive care are sepsis, respiratory failure requiring mechanical ventilation, low serum albumin and a high acute physiology and chronic health evaluation II (APACHE II) score. The initiation of HAART for improving prognosis depends on the clinician assessment.

Risks and mechanisms of disease transmission

There always remains a high risk of HIV transmission in anesthetic practice. HIV infection can be transmitted from patient through sharp injuries, broken skin contact with body fluids and splashing of mucosal surfaces. The risk of transmission by needle stick injury may be between 0.03 and 0.3% depending on factors like hollow needle injury, volume of blood inoculated and depth of needle puncture. The possible risk of HIV transmission from patient to patient results from reuse of syringes, airway devices or respiratory circuits. Disposable circuits and use of hydrophobic filters should be instituted in an infected patient. Laryngoscopes should be properly sterilized before reuse. The risk of HIV transmission from anesthesiologist to patient is estimated at around 2.4-24 per million procedures.

All types of in hospital transmission of HIV infection can be effectively reduced by implementing ‘Universal Precautions’ which is defined by CDC as set of precautions designed to prevent transmission of HIV infection to health workers while providing health care.[37] It involves proper handling of blood, body fluids containing semen, blood, tissues, cerebrospinal fluid, pleural fluid, peritoneal, pericardial, and amniotic fluids. Various measures described are washing hands, wearing double gloves, eye protection, feet protection, proper handling of needles and sharps, and proper sterilization of instruments and linen.

Post-exposure prophylaxis

The health workers are in a constant danger of exposure to an HIV infected patient as they are involved in the care of such patients. The need to start the post-exposure prophylaxis for these exposed health workers depends upon:

Nature of inoculums, i.e., percutaneous or mucosal splash, large or small volume of blood and hollow or closed needle injuries.

Patient's viremic status, i.e., HIV negative, unknown or HIV positive.

The need for post-exposure prophylaxis should be ascertained by a team of experts keeping in mind all the factors involved in transmission of disease and it should be started within 72 hours of exposure and can be continued for four weeks. The variousrecommendations for post-exposure prophylaxis are summarized in following table [Table 4].[3839]

Table 4

Showing post-exposure recommended prophylaxis for HIV

Basic two drug regimen: Zidovudine 600 mg/day in divided doses + Lamivudine 150 mg twice a day.

Expanded three drug regimens: Basic two drug regimen + one of the following:

Indinavir 800 mg three times a day on an empty stomach.

Nelfinavir 750 mg three times a day with meals.

Efavirenz 600 mg once a day at bed time

Abcavir 300 mg two times a day.

Nevirapine (NNRTI) is usually not recommended for post-exposure prophylaxis.

Post-exposure prophylaxis in pregnancy

If the pregnant female is exposed, the decision to initiate the therapy should be taken after thorough discussion and after weighing the potential risks and benefits to the mother and fetus. The following drugs should be avoided in pregnancy:

Efavirenz due to its suspected teratogenicity in animals.

Combination of stavudine and didanosine due to its potential to cause severe lactic acidosis.

Indinavir due to the risk of hyperbilirubinemia in newborn.

Blood transfusion and HIV

Scientific data exists for the immunomodulatory effect of allogenic blood transfusion known as Transfusion Related Immunomodulation (TRIM).[40] It has been suggested that there is an increase in viral load in patients with advanced HIV infection with the use of blood transfusion and hence it should be used cautiously if need arise.[41]

Pain related to HIV infection

HIV infection is often accompanied with both acute and chronic pain whose etiology is multifactorial which includes opportunistic infections like herpes simplex, peripheral neuropathy, HIV related arthralgia or drug related pain. The pain associated with HIV infection is often debilitating and is mostly undertreated. The approach towards treatment of HIV related pain should be multidisciplinary and should be given equal importance as that of the treatment of HIV.

Conclusions

HIV infection has become a growing danger to the humanity and the anesthesiologist is often faced with difficulty in managing such patients for various surgeries. The anesthetic technique should be chosen keeping in mind various implications of this disease on the body. The care of such patients in intensive care also should be done with all the universal precautions to reduce the cross infection to health care personnel.