12 Intensive care

Authors


*E-mail: simon.edwards2@nhs.net

12.1 Background

From the start of the HIV epidemic, respiratory failure has been the most common indication for patients with HIV infection to be admitted to the intensive care unit (ICU). In the era of highly active antiretroviral therapy (HAART), Pneumocystis jirovecii pneumonia (PCP), bacterial pneumonia and tuberculosis continue to be significant causes of respiratory failure; however, admission to the ICU with non-HIV-associated respiratory causes, including emphysema and asthma, is increasingly encountered [1–3]. An emerging cause of respiratory failure requiring admission to the ICU is immune reconstitution inflammatory syndrome (IRIS) [4]. Non-respiratory causes, including renal and hepatic failure, cardiac disease, drug overdose and severe toxicity from HIV therapy are increasingly recognised [1–4].

Early in the HIV epidemic, HIV-seropositive patients with critical illnesses were deemed incurable. ICU mortality rates were high and long-term survival rates were low [5–7]. The majority of admissions to the ICU were patients with severe PCP. As a direct result of HAART, there has been a sustained reduction in HIV-associated morbidity and mortality. Several studies report improved outcomes for HIV-seropositive patients requiring admission to the ICU in the HAART era [1–3,8,9]. One recent study suggests that outcomes from ICU admission for HIV-seropositive patients are equivalent to those for the general medical (non-HIV-infected) population [3].

  • HIV-seropositive patients should not be refused ICU admission based merely on the patient's HIV-serostatus (category IV recommendation).

Improved survival from HIV-associated PCP after 1996 has been shown to be independent of the use of HAART and likely reflect general improvements in the ICU management of acute lung injury (ALI) [10].

  • All HIV-seropositive patients with ALI/acute respiratory distress syndrome (ARDS) who are mechanically ventilated should be managed using the same protocols for management of ALI/ARDS as among general populations – with low tidal volumes and controlled plateau pressures, for example using the ARDS Network guidelines [11] (category IV recommendation).

12.2 Antiretroviral therapy on the ICU

It is currently unclear whether starting HAART on the ICU confers improved outcome for HIV-seropositive patients admitted to the ICU [1,3,10]. In such patients, the short-term effect of HIV RNA level and CD4 cell count on mortality is unclear. Among HIV-seropositive patients already in receipt of HAART, there was no apparent improvement in survival when compared with HIV-seropositive patients not taking HAART [3]. The use of HAART in severely unwell HIV-seropositive patients is confounded by several issues, including drug absorption, requirements for dose modification in the presence of intercurrent renal- and hepatic-induced disease, drug–drug interactions (see Table 12.1), HAART-associated toxicity and IRIS. In some circumstances it may be more appropriate to change HIV therapy rather than dose modify. Advice should be sought from an HIV clinician and/or pharmacist prior to planned modification of HAART.

Table 12.1.   Potential ICU and antiretroviral drug interactions
Drug nameInteraction with antiretroviralAction required
  1. Antiretroviral drugs, especially the NNRTIs and boosted PIs, have several important drug–drug interactions. This table lists some examples of drug–drug interactions with antiretrovirals and drugs used in intensive care. As data and advice changes frequently, this information should always be interpreted in conjunction with the manufacturer's information (http://www.medicnes.org.uk). Other useful web-based reference sources include the Liverpool HIV drug information website (http://www.hiv-druginteractions.org) and the Toronto Clinic (http://www.hivclinic.ca/main/drugs_interact.html).

Antibiotics
 ClarithromycinNNRTIs, PIs and boosted PIs can alter clarithromycin levelsSee individual antiretroviral manufacturer's information
Zidovudine levels may be decreasedSeparate dose interval by 1–2 h
Maraviroc likely to be increasedReduce dose of maraviroc (150 mg od)
 RifabutinBoosted PIs increase rifabutin levelsReduce rifabutin dose (150 mg three times a week)
NNRTIs can reduce rifabutin levelsConsider increasing rifabutin dose (450 mg od)
Etravirine and rifabutin levels reduced when used togetherUse with caution
 RifampicinNNRTI levels reduced.Increase dose of efavirenz (800 mg od depending on patient's weight)
Contraindicated with etravirine and nevirapine (some units increase nevirapine dose)
PI levels significantly reducedNot recommended to be used together. Seek HIV specialist pharmacist advice
Maraviroc levels reducedIncrease maraviroc dose (600 mg bd)
Raltegravir levels reducedIncrease dose of raltegravir (800 mg bd)
Antifungals
 AmphotericinTenofovirCaution – increased risk of renal toxicity with concurrent or recent use.
 ItraconazoleRitonavir increases itraconazole exposureAvoid high doses of itraconazole
Caution with boosted PIs – some PI levels increased
Efavirenz, etravirine and nevirapine reduce itraconazole levelsConsider alternative, or increasing dose.
Monitor clinical effect
Maraviroc levels increasedReduce maraviroc dose (150 mg BD)
 VoriconazoleEfavirenz levels increased and voriconazole levels reducedNot recommended to be used together. Seek HIV specialist pharmacist advice
Etravirine and voriconazole levels are both increasedNo dose adjustment required – monitor
Voriconazole levels reduced by lopinavir/ritonavirNot recommended to be used together. Seek HIV specialist pharmacist advice
 FluconazoleZidovudine levels increasedCaution – monitor for adverse effects
Nevirapine levels increasedCaution – monitor for adverse effects
 PosaconazoleEfavirenz reduces posaconazole levelsAvoid combination unless benefit to patient outweighs risk
 CaspofunginEfavirenz and nevirapine reduce levels.Increase caspofungin dose to 70 mg od, for those <80 kg
Acid-lowering agents
 H2 receptor blockersAtazanavir levels reducedCaution if used together. Temporal separation should be considered.
 Proton pump inhibitorsAtazanavir levels significantly reducedNot recommended to be used together. Seek HIV specialist pharmacist advice
Saquinavir levels significantly increased by omeprazoleNot recommended to be used together. Seek HIV specialist pharmacist advice
Raltegravir levels increased with proton pump inhibitorsClinical significance unknown
Anticonvulsants
 NNRTIs decrease levels of anticonvulsants such as carbamazepine, phenytoin and phenobarbital and anticonvulsants may reduce the levels of NNRTIsNot recommended to be used together. Seek HIV specialist pharmacist advice. Use new anticonvulsant agents (e.g. vigabatrin, gabapentin)
PIs and boosted PIs can increase levels of anticonvulsants such as carbamazepine, phenytoin and phenobarbital, as well as reduction in PI levelsNot recommended to be used together. Seek HIV specialist pharmacist advice. Use new anticonvulsant agents (e.g. vigabatrin, gabapentin)
HMG CoA reductase inhibitors
 SimvastatinPIs and boosted PIs significantly increase simvastatin levelsAvoid simvastatin. Use low-dose pravastatin or low-dose atorvastatin. Dose titrate upwards. See individual drug manufacturer's literature
NNRTIs reduce statin levelsSee individual drug manufacturer's literature. Seek HIV specialist pharmacist advice
Others
 WarfarinRitonavir reduces effect of warfarinFrequent INR monitoring initially
Efavirenz and nevirapine have unpredictable effect on warfarinFrequent INR monitoring initially
Etravirine may increase warfarin effectFrequent INR monitoring initially
 BenzodiazepinesPIs increase diazepam levelsManufacturers do not recommend coadministration. Use with caution and dose reduction
NNRTIs decrease diazepam levelsUpward dose titration may be required
PIs (boosted) increase midazolam levelsNot recommended to be used together. Seek HIV specialist pharmacist advice
NNRTIs potentially decrease midazolam levels.Upward dose titration required
 AntiarrhythmicsEtravirine decreases levels of amiodarone and flecainide and other drugs in this classUse with caution
PIs can increase levels of amiodarone and flecainideNot recommended to be used together. Seek HIV specialist pharmacist advice
Efavirenz increases levels of amiodarone and flecainide.Not recommended to be used together. Seek HIV specialist pharmacist advice
  • Expert daily consultation between HIV and ICU physicians is essential in the management of critically-ill HIV-seropositive patients admitted to the ICU. Additionally, the advice of a pharmacist with expertise of treatment of HIV-associated infection should be sought. In some cases this expertise will be obtained by transfer of the patient to a tertiary centre (category IV recommendation).

Ancillary