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''Originally from Update in Anaesthesia | www.wfsahq.org/resources/update-in-anaesthesia''

S Wilson* and S Patel (*Correspondence Email: wdrsam@googlemail.com)

Wilson S
::Consultant in Anaesthesia,
::Hampshire Hospitals
::Foundation Trust


S Patel
::Consultant in Paediatric
::Infectious Diseases and
::Immunology
::Southampton Children’s
::Hospital

Based in part upon: [https://www.wfsahq.org/documents/Update%20in%20Anaesthesia/update%20025%201%202009.pdf Wilson S. HIV and Anaesthesia. Update in Anaesthesia 2010; 25,1: 25-29.]
----
Summary

It is estimated that 3.3 million
children under 15 years of
age are living with HIV, the
vast majority of them in sub-
Saharan Africa. A significant
number of these children will
require surgery. It is essential
to understand the implications
for anaesthesia in order to
formulate an appropriate
anaesthetic management plan.
In order to safely anaesthetise
an HIV-infected child,
we require a reasonable
understanding of HIV infection:
its pathophysiology, potential
multisystem complications
and the pharmacology of ART.
An accurate assessment of the
child with HIV may affect your
choice of anaesthesic agents,
how to manage pain including
whether to use regional
anaesthesia, approaches to
infection control, and general
issues surrounding perioperative
care.

----

It is estimated that 3.3 million children under 15 years
of age are living with HIV, the vast majority of which
are in sub-Saharan Africa. Due to improved HIV
prevention a 35% reduction in numbers from 2009
means that in 2012 approximately 260,000 children
under 15 were diagnosed with HIV and 647,000
children were receiving antiretroviral therapy (ART).
A significant number of these children will require
surgery for elective or emergency procedures, either
directly related or unrelated to HIV. For this reason, it
is essential for us to fully understand the implications
for anaesthesia. In order to safely anaesthetise an HIVinfected
child, we require a reasonable understanding
of HIV infection: its pathophysiology, multisystem
complications and the pharmacology of ART. An
accurate assessment of the child with HIV can
potentially impact upon your choice of anaesthesic
agents, whether to use regional anaesthesia, how to
manage pain, approaches to infection control and
general issues surrounding peri-operative care.

=PATHOGENESIS, AETIOLOGY AND CLASSIFICATION=
HIV is a single-stranded RNA virus with HIV-1 and
HIV-2 types and multiple subtypes recognised. These
subtypes express differences in geographical prevalence
as well as disease progression and transmission
rates. Like other retroviruses, HIV contains the
enzyme reverse transcriptase that enables viral RNA
to be transcribed to DNA, which then becomes
incorporated into the host cell genome and is able
to replicate freely. Inhibition of this viral replication
process is the target of ART. HIV preferentially
infects T helper lymphocytes (CD4+ T cells) and
leads to their progressive quantitative and qualitative
destruction. This makes the host increasingly
immunocompromised, and thus more susceptible to
opportunistic infections and malignancies.

More than 80% of HIV infections in children
are due to vertical transmission (ie.trans-placental
exposure to maternal HIV during the perinatal
period). Perinatal transmission can occur during any
one of three phases: in utero, during the peripartum
period, or during breastfeeding. The risk of perinatal
acquisition without intervention (such as maternal
ART, caesarean delivery, avoidance of breast milk) is
25-40%. Other routes of transmission, as for adults,
are sexual or via contaminated blood through the
administration of blood products, organ donations or
by sharing contaminated needles during intravenous
drug use.

The Centers for Disease Control and Prevention
(CDC) classification system (Table 1) clearly shows
the increasing severity of symptoms as HIV infection
progresses.

=MULTI SYSTEM INVOLVEMENT=
In order to perform a thorough preoperative
assessment of the child with HIV, it is important that
you appreciate which organ systems may be affected,
either as a direct consequence of HIV infection
(opportunistic infection / malignancy), or indirectly
such as from side effects of ART, chemotherapy or
anti-infective agents. Awareness of these effects allows
us to appropriately adapt our anaesthetic.
Haematological system
The haematological system can be greatly affected
during HIV infection; anaemia, neutropaenia
and thrombocytopaenia are common. Persistent
generalised lymphadenopathy may be a feature and
may also be the target of surgery for the affected child
in the early stages of disease for diagnostic purposes.
Haematological malignancies are often seen as are
coagulation abnormalities, with obvious implications
for surgical and anaesthetic interventions.
Cardiovascular system
The cardiovascular system may be affected in a number
of ways in an HIV-infected child. The pericardium,
myocardium or endocardium may be involved or
there may be vascular lesions or neoplasms. Important
and common cardiovascular complications that have
major implications for patient management are:
::• Pulmonary hypertension
::• Pericardial effusions
::• Endocarditis and valvular lesions
::• Vasculitis
::• Cardiomyopathies.


----
Table 1. ''CDC classification of paediatric HIV infection''
----
{|
! style="text-align:left;"|Category
!Associated symptoms
|-
|'''N - Asymptomatic''' 
|No symptoms
|-
|
|1 category A symptom only.
|-
|'''A - Mild symptoms''' 
|2 or more of the following symptoms:
|-
|
|Lymphadenopathy
|-
|
|Hepatomegaly
|-
|
|Splenomegaly
|-
|
|Dermatitis
|-
|
|Parotitis
|-
|
|Recurrent or persistent upper respiratory infection, sinusitis, or otitis media.
|-
|'''B - Moderate symptoms'''
|Anaemia, neutropenia, or thrombocytopenia
|-
|
|Bacterial meningitis, pneumonia, or sepsis
|-
|
|Candidiasis, oropharyngeal (thrush),
|-
|
|Cardiomyopathy
|-
|
|Cytomegalovirus infection, with onset before 1 month
|-
|
|Diarrhoea, recurrent or chronic
|-
|
|Hepatitis
|-
|
|Herpes simplex virus (HSV) stomatitis, recurrent
|-
|
|HSV bronchitis, pneumonitis, or oesophagitis
|-
|
|Herpes zoster (shingles)
|-
|
|Leiomyosarcoma
|-
|
|Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia complex
|-
|
|Nephropathy
|-
|
|Nocardiosis
|-
|
|Persistent fever
|-
|
|Toxoplasmosis
|-
|
|Varicella, disseminated (complicated chickenpox).
|-
|'''C - Severe symptoms:'''
|Serious bacterial infections, multiple or recurrent
|-
|
|Candidiasis, oesophageal or pulmonary
|-
|
|Coccidioidomycosis, disseminated
|-
|
|Cryptococcosis, extrapulmonary
|-
|
|Cryptosporidiosis or isosporiasis
|-
|
|Cytomegalovirus disease
|-
|
|Encephalopathy
|-
|
|Herpes simplex virus infection
|-
|
|Histoplasmosis, disseminated
|-
|
|Kaposi’s sarcoma
|-
|
|Lymphoma
|-
|
|Mycobacterium tuberculosis, disseminated or extrapulmonary
|-
|
|Mycobacterium, other species disseminated
|-
|
|Mycobacterium avium complex or Mycobacterium kansasii
|-
|
|Pneumocystis carinii pneumonia
|-
|
|Progressive multifocal leukoencephalopathy
|-
|
|Salmonella (nontyphoid) septicemia, recurrent
|-
|
|Toxoplasmosis of the brain.
|-
|}
----
==Respiratory system==
Both the upper and lower airway can be involved in HIV infection
in children, and respiratory symptoms are a common presenting
complaint. These include:
::• Upper respiratory tract infections (chronic otitis media)
::• Bacterial pneumonia
::• Atypical infections (commonly tuberculosis, nontuberculous mycobacteria, and fungal infections)
::• Lymphocytic interstitial pneumonia (LIP)
::• Bronchitis
::• Sinusitis
::• Airway obstruction.
==Gastrointestinal system==
Commonly encountered complications of the gastrointestinal tract
associated with HIV infection and its treatment can have major
effects on the metabolism of our anaesthetic agents and any other
drugs used. These effects include:
::• Poor nutritional status with resultant delayed healing times
::• Difficulty or pain on swallowing
::• Increased gastric emptying times.
Acute or chronic diarrhoea is common, with associated dehydration
and electrolyte dysfunction and in addition, there can be hepatobiliary
and pancreatic impairment.
==Renal system==
Acute and chronic renal disease can be associated with HIV. Potential causes of renal impairment include:
::• Drug induced nephrotoxicity
::• Hypertension
::• Diabetes
::• HIV-associated nephropathy.
It is important to avoid nephrotoxic drugs where possible in these
children and to dose adjust renally excreted drugs and adequately
hydrate the child in order to prevent further renal damage.
==Neurological system==
HIV can affect the neurological system directly (HIV encephalopathy)
or indirectly via opportunistic infections, neoplasms or immune
deficiency. These can involve all structures including the meninges,
brain, spinal cord, peripheral nerve or muscle. Neurocognitive
impairment, developmental delay, encephalopathy, autonomic
neuropathy and seizures are all recognised complications of HIV
which have important implications in our clinical management.
Full neurological examination pre-operatively with appropriate
documentation is essential especially if you plan to use regional
anaesthesia.
==Endocrine and metabolic system==
ART has common endocrine side effects including lipodystrophy,
insulin resistance (metabolic syndrome), hypothalamic-pituitaryadrenal
axis dysfunction, hypo- or hyperthyroidism and lactic
acidosis.
=ANTIRETRO VIRAL THERAPY=
The use of a combination ART or highly active antiretroviral therapy
(HAART) has been a major advance in the treatment of HIV
infection. These drugs are classified into the following five classes
according to the mechanisms of inhibition of viral replication (Table
2):
::• Reverse transcriptase enzyme inhibitors
::• Protease enzyme inhibitors
::• Integrase inhibitors
::• Entry inhibitors
::• Fusion inhibitors.
Adherence to antiretroviral therapy is of paramount importance;
adherence levels below 95% are associated with increases in viral load
and drug resistance. This naturally has implications for interruption
of ART due to perioperative fasting. Fasting times should be kept to
an absolute minimum.
Many adverse side effects are associated with ART and you should
look for these during preoperative assessment. They can be divided
broadly into four groups:
::• Allergic reactions: skin rashes and hypersensitivity responses
::• Bone marrow suppression: anaemia, neutropaenia and thrombocytopaenia.
::• Metabolic abnormalities: fat maldistribution and change in body habitus, dyslipidaemia, hyperglycaemia and insulin resistance, bone disorders e.g. osteopaenia, osteoporosis and osteonecrosis
::• Mitochondrial dysfunction: lactic acidosis, hepatic toxicity, pancreatitis, peripheral neuropathy.

Anaesthetic drugs may interact with ART. Anaesthetic agents may
induce pharmacodynamic changes to affect their efficacy and toxicity
via cytochome p450 induction/inhibition, and the pharmacokinetic
effects of ART can affect the absorption, distribution, metabolism
and elimination of anaesthetic and analgesic drugs.
Pharmacodynamic interactions can be managed by avoiding
anaesthetic agents such as halothane or methoxyflurane that cause
hepatic or renal dysfunction. Propofol and NRTIs may both
potentially promote mitochondrial toxicity and lactic acidosis,so it
may be wise to avoid propofol infusions in patients receiving ART
due to the already potentially compromised mitochondrial function.
Pharmacokinetic interactions are more complex and are primarily
due to liver enzyme induction or inhibition, particularly of the
CYP450 3A4 enzyme. Protease inhibitors (PIs) and NNRTIs are the
most commonly implicated groups of drugs. Enzyme induction or
inhibition can affect the action of several classes of anaesthetic drugs:
::• Opioids. The effects of fentanyl may be enhanced by ritonavir due to both liver enzyme inhibition and induction. Enzyme inhibition reduces fentanyl clearance and enzyme induction increases metabolism to active metabolites such as normepiridine.
::• Benzodiazepines Saquinavir may inhibit midazolam metabolism.
::• Local anaesthetics such as lignocaine may have increased plasma levels due to enzyme inhibition with direct implications for toxic doses.
::• Neuromuscular blocker effects may be prolonged, even after a single dose.
::• Calcium channel blockers may have enhanced hypotensive effects due to enzyme inhibition.
These interactions are complicated and multiple and databases
exist that describe these interactions in detail (such as www.hivdruginteractions.
org).Evidence for interactions specifically with
anaesthetic drugs is relatively sparse.

----
''Table 2. ART''
----
{|
! style="text-align:left;"| Drug class
! Available drugs
|-
|'''1. Reverse transcriptase inhibitors'''
|-
|Nucleoside/nucleotide analogues (NRTIs)
|Abacavir (ABC)
|-
|
|Didanosine (ddI)
|-
|
|Emtricitabine (FTC)
|-
|
|Lamivudine (3TC)
|-
|
|Stavudine (d4T)
|-
|
||Zidovudine (AZT, ZDV)
|-
|Non-nucleotide reverse transcriptase Inhibitors (NNRTIs)
|Delavirdine (DLV)
|-
|
|Efavirenz (EFV)
|-
|
|Etravirine (ETR)
|-
|
|Nevirapine (NVP)
|-
|'''2. Protease inhibitors (PIs)'''
|Atazanavir (ATV)
|-
|
|Darunavir (DRV)
|-
|
|Fosamprenavir (FPV)
|-
|
|Indinavir (IDV)
|-
|
|Lopinavir (LPV)
|-
|
|Nelfinavir (NFV)
|-
|
|Ritonavir (RTV)
|-
|
|Lopinavir/ritonavir (LPV/r)
|-
|
|Saquinavir (SQV)
|-
|
|Tipranavir (TPV)
|-
|
|Amprenavir (APV)
|-
|'''3. Integrase inhibitors
|Raltegavir (RAL)'''
|-
|
|Dolutegravir
|-
|'''4. Entry inhibitors'''
|-
|CCR 5 antagonists
|Maraviroc (MVC)
|-
|'''5. Fusion inhibitors'''
|Enfuviritide (ENF, T-20)
|-
|}
----



Due to the risk of developing resistance if doses are missed, it is
recommended that ART be continued throughout the perioperative
period if at all possible. Naturally this needs to be compatible with
the proposed surgery and with the patient’s gastrointestinal function.
Some drugs are available in liquid form enabling administration via
nasogastric feeding tube or gastrostomy. Parenteral preparations are
limited to zidovudine and enfuvirtide only.
=REGIONAL ANAESTHESIA=
The presence of HIV infection is not an absolute contraindication to
regional anaesthesia and there is no evidence that HIV progression
is increased by central neuraxial blockade. Regional anaesthesia may
be relatively contraindicated with several pathologies associated with
HIV infections such as myelopathy, vertebral or spinal neoplasms,
CNS infections and coagulopathies, as well as in the severely
immunocompromised patient. You must conduct a full preoperative
neurological assessment and document any pre-existing neurological
deficit if you plan a regional anaesthetic technique.
=BLOOD TRANSFUSION=
There is evidence that allogeneic blood transfusion in the HIV
infected patient can lead to transfusion-related immunomodulation
(TRIM) and can result in an increase in HIV viral load. Blood
should therefore only be transfused where unavoidable to maintain
patient safety.
=PAIN=
Pain is common in advanced HIV disease and can be very difficult
to treat. The aetiology of this pain can be multifactorial, including:
::• Opportunistic infections such as herpes simplex
::• HIV-related arthralgia
::• Peripheral neuropathy
::• Drug-related pain.
Pre-existing pain and its treatment can affectthe treatment of
postoperative pain and will necessitate a multimodal approach.
=INFECTION CONTROL=
Infection control is an important issue both for the protection of the
immunocompromised child from opportunistic infections, as well as
for the professionals caring for the child during any procedures. Use
a strict aseptic technique for all procedures.
The cumulative risk of contracting HIV over an anaesthetic
career can be as high as 4.5%. This can occur due to a needlestick
injury (transmission risk of 0.3%); the risk is increased if there is
a higher volume of blood injected, such as with hollow needles or
deep punctures. Risk of transmission via the mucocutaneous route
(splashing of a mucosal surface or broken skin by body fluid) is
extremely low (0.03%).

There are universal precautions that should be taken to reduce the risk of HIV transmission to healthcare workers:
::• Dispose of sharps safely (into a rigid locking container prior to incineration)
::• Do not re-sheath needles
::• Wear gloves
::• Cover any cuts or broken skin with an impermeable dressing
::• Strongly consider eyeshields and facemasks
::• Use disposable equipment where possible; clean reusable equipment properly.

Post-exposure prophylaxis for healthcare workers should be available
and should commence as soon as possible after potential high risk
exposure (ideally within the first 1-2hrs).

If tuberculosis is suspected or likely in a patient known to have HIV,
all healthcare workers should wear a tight fitting facemask to reduce
the risk of transmission (ideally a high quality particulate mask if
available e.g. N95 or HEPA).

=APPROACH TO FORMULATING AN ANAESTHETIC MANAGEMENT PLAN FOR THE HIV-INFECTED CHILD=
A multisystem and multidisciplinary approach is recommended.
Thorough preoperative assessment for status of HIV infection:
::• History, including risk factors (for child & parents)
::• Physical examination
::• Laboratory tests
::• Assess organ involvement
::• Drug history and side effects.

Investigations ideally include:
::• Full blood count
::• Clotting function to exclude coagulation abnormalities (consider use of TEG/platelet mapping if available)
::• Biochemical tests including glucose, electrolytes, renal & liver function to exclude possible metabolic, liver or renal disturbances
::• Viral load and CD4 count
::• Chest radiography to screen for opportunistic infections and tuberculosis
::• Cardiac evaluation with electrocardiography and echocardiography (if possible) to screen for cardiomyopathy. Preparation of operating theatre and personnel:
::• Infection control preparation including universal precautions with gloves, aprons, visors available
::• Sharp object collection devices with appropriate sharps handling (no re-sheathing of needles)
::• Staff fully aware of protocols in the event of occupational exposure
:::- Rinse and wash affected area with soap & water
:::- Recipient lab tests: HIV, acute hepatitis panel
:::- Determine infectious status of source
::• Availability of post exposure prophylaxis to be started as soon as possible following accidental high risk exposure (ideally within 1 hour of exposure)
:::- HIV PEP protocol with 3 or more antiretroviral drugs if known HIV positive donor or high-risk patient or with 2 or more if low risk. ART is given for 4 weeks or until source is found to be negative for HIV
:::- Follow up with counselling and HIV testing for at least 6 months post exposure (tests done at baseline, 6 weeks, 12 weeks and 6 months)
:::- Hepatitis B immune globulin +/or hepatitis B vaccine
:::- Achieve early identification of chronic hepatitis C disease.

Perioperative considerations for the child with HIV:
::• Minimise interruptions in ART as far as possible to diminish the risk of developing drug resistance
::• Consider drug interactions between ART and drugs affected by hepatic enzyme inhibition and/or induction
::• Exercise strict aseptic technique as HIV infected children are immunocompromised and are susceptible to opportunistic infections
::• Additional emotional and psychological support may be necessary as primary caregivers may have been affected by HIV/AIDS
::• The anaesthetic plan should of course be tailored to the individual child and the type of surgery to be undertaken.


=REFERENCES AND FURTHER READING=
::Bayer R: Discrimination, informed consent, and the HIV infected clinician. British Medical Journal 1997; 314: 915-6.
::Centers for Disease Control and Prevention. HIV/AIDS Surveillance Report 2004. Vol. 16. Atlanta, Ga: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2005. 1-46.
::Diprose P, Deakin CD and Smedley J. Ignorance of post-exposure prophylaxis guidelines following HIV needlestick injury may increase the risk of seroconversion. British Journal of Anaesthesia 2000; 84: 767-70.
::Horlocker TT and Wedel DJ. Regional Anaesthesia in the Immunocompromised Patient. Regional Anaesthesia and Pain Medicine 2006; 31: 334-45.
::Joint WHO/United Nations programme on HIV/AIDS; 2008 report on global AIDS epidemic. www.unaids.org
::Kharasch ED, Mitchell D, Coles R and Blanco R. Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir; . Antimicrobial Agents and Chemotherapy 2008; 52:1663-9.
::Kuczkowski KM. Anaesthetic considerations for the HIV-infected pregnant patient. Yonsei Medical Journal 2004; 45:1-6.
::Leelanukrom R: Anaesthetic considerations of the HIV-infected patients. Current Opinion in Anaesthesiology 2009, 22: 412-418.
::Leelanukrom R and Pancharoen C. Anaesthesia in HIV-infected children. Pediatric Anaesthesia 2007; 17: 509-19.
::Parthasarathy S and Ravishankar M: HIV and anaesthesia; Indian Journal of Anaesthesia 2007; 51: 91-99.