Introduction
Medication administration during critical illness
Drug | Oral suspension available | Intravenous formulation available | Data supporting enteral drug administration |
---|---|---|---|
Yes | Yes (dosage is 10 mg every 8 hours) | Reports exist where sildenafil tablet was crushed, dissolved in 5 ml sterile water and administered via enteral tube | |
Noa | No | No data available. May be reasonable to use extemporaneous preparation of tadalafil suspension for enteral administration | |
Noa | No | Institute for Safe Medication Practices does not recommend crushing due to teratogenic propertiesb | |
No | No | Institute for Safe Medication Practices: `do not crush medication’ (extended release product with teratogenic properties); do not administer via enteral tube | |
Macitentan [18] | No | No | Manufacturer recommends that tablets not be split, chewed or crushed; do not administer via enteral tube |
Riociguat [19] | No | No | No data available; would not recommend crushing due to teratogenic properties |
Bacteremia and sepsis
Catheter type | Catheter volume |
---|---|
55 cm PICC line, 17 gauge lumen | 0.76ml [28] |
55 cm PICC line, 18 gauge lumen | 0.56 to 0.68ml [28] |
55 cm PICC line, 19 gauge lumen | 0.44ml [28] |
Single-lumen Hickman catheter, 9.6 French | 1.8ml [28] |
Double-lumen Hickman catheter, 9 French | 0.6ml (small port), 1.3ml (large port) [28] |
Triple-lumen catheter | 0.38ml (18 gauge ports), 0.42ml (16 gauge ports) [29] |
Altered mental status
Need for gastrointestinal rest
Acute renal insufficiency/failure
Drug | Degree of renal elimination | Dosage adjustments | Monitoring | Recommendations |
---|---|---|---|---|
Phosphodiesterase type 5 inhibitors
| ||||
Sildenafil [8] | Nonrenal metabolism to active metabolites; 13% of dose excreted in urine as metabolites | No dose adjustment is required. In patients with CrCl ≤30 ml/minute, exposure to parent drug and active metabolite increased twofold | Worsening of side effects (hypotension, epistaxis, nasal congestion, headache, dyspepsia, flushing, insomnia, erythema, dyspnea and/or rhinitis) | Monitor for worsening of side effects and decrease dosage if indicated. |
Tadalafil [11] | Nonrenal metabolism; however, renal impairment results in twofold to fourfold increase in tadalafil exposure | CrCl 31 to 80 ml/minute: start dosing at 20 mg once daily; increase to 40 mg once daily based on individual tolerability. CrCl ≤30 ml/minute or hemodialysis: avoid use. | Worsening of side effects (hypotension, headache) | Monitor for hypotension, consider dose reduction. Severe impairment: hold dose if side effects worsened |
Endothelin-receptor antagonists
| ||||
Ambrisentan [17] | Nonrenal elimination | No adjustment for mild-moderate renal failure; severe renal failure and hemodialysis not studied | Fluid overload | Hold if fluid overload is problematic |
Bosentan [13] | <3% eliminated in urine | No adjustment necessary | Fluid overload | Hold if fluid overload is problematic |
Macitentan [13] | Nonrenal elimination | No adjustment necessary | Worsening of side effects (anemia, nasopharyngitis, pharyngitis, bronchitis, headache, influenza, and urinary tract infection) | Likely safe to use in patients with renal dysfunction |
Soluble guanylate cyclase stimulator
| ||||
Riociguat [19] | 40% drug eliminated in urine (mostly as inactive metabolites) | Not recommended in patients with CrCl <15 ml/minute or those receiving dialysis | Possible hypotension bleeding or other side effects (headache, dizziness, dyspepsia/gastritis, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation) | Monitor for hypotension, consider dose reduction. Severe impairment (anuria): hold dose if side effects worsened |
Intravenous prostacyclin therapy
| ||||
Nonrenal elimination; metabolites recovered in urine, some of which are minimally active | No adjustment necessary; if initiating therapy, consider starting at a low dose and titrating slowly | Possible hypotension or side effects (headache, jaw pain, flushing) | Titrate slowly during initiation phase; consider gradual dosage reduction if patient is hypotensive and experiencing increased side effects (flushing, headache, jaw pain); do not abruptly discontinue therapy | |
Treprostinil [41] | 4% of unchanged drug eliminated in urine; all metabolites (inactive) renally eliminated | No specific recommendation available | Possible hypotension or side effects (headache, jaw pain, flushing) | Titrate slowly during initiation phase; consider gradual dosage reduction if patient is hypotensive and is experiencing increased side effects (flushing, headache, jaw pain); do not abruptly discontinue therapy |
Inhaled vasodilators (prostacyclin and nonprostacyclin)
| ||||
Inhaled nitric oxide [42] | Combines with oxyhemoglobin to produce methemoglobin and nitrate; nitrate is renally eliminated | No dosage adjustments recommended/required | Methemoglobin | Probably safe to use in patients with renal dysfunction |
Treprostinil, inhaled [21] | 4% of unchanged drug eliminated in urine; all metabolites (inactive) renally eliminated | No specific recommendation available | Possible hypotension or side effects (headache, jaw pain, flushing) | Titrate slowly during initiation phase; consider increasing dosing interval if patient is hypotensive and experiencing increased side effects (flushing, headache, jaw pain) |
Iloprost, inhaled [20] | Nonrenal elimination | Not studied in patients with renal impairment; based on drug elimination, accumulation not expected | Possible syncope or side effects (headache, flushing, dizziness, nausea, vomiting or diarrhea) | Probably safe for use in patients with renal dysfunction. Continue usual monitoring |
Acute hepatic impairment/failure
Drug | Degree of hepatic elimination | Dosage adjustments | Monitoring | Recommendations |
---|---|---|---|---|
Phosphodiesterase type 5 inhibitors
| ||||
Sildenafil [8] | Extensive hepatic metabolism (CYP3A4 major; CYP2C9 minor); active metabolite (which is 50% ==as active as sildenafil) also undergoes hepatic metabolism | No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied | Hypotension; worsening of side effects (epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea and/or rhinitis) | Hold or reduce dose if patient presents with acute liver injury and hypotension. |
Tadalafil [11] | Hepatic metabolism via CYP3A to inactive metabolites (which undergo methylation and glucuronidation) | Child-Pugh class A or B: reduce starting dose to 20 mg once per day | Hypotension; worsening of side effects (headache) | Hold or reduce dose if patient presents with acute liver injury and hypotension |
Child-Pugh class C: avoid use | ||||
Endothelin-receptor antagonists
| ||||
Ambrisentan [17] | Hepatic metabolism via CYP3A, CYP2C19, and UGTs 1A9S, 2B7S an 1A3S; substrate OATP1B1 and OATP1B3; substrate but not an inhibitor of P-glycoprotein | Not recommended in patients with moderate or severe hepatic impairment | Peripheral edema/fluid overload, nasal congestion, sinusitis and/or flushing | Package labeling recommendation: discontinue if aminotransferase elevations >5× ULN or if elevations are accompanied by bilirubin >2× ULN, or by signs or symptoms of liver dysfunction and other causes are excluded |
Bosentan [13] | Eliminated by biliary excretion following metabolism in the liver; three metabolites (one active); induces CYP2C9, CYP34 and possibly CYP2C19. Thought to induce its own metabolism | Child-Pugh class A: no dosage adjustment required | Peripheral edema/fluid overload, anemia, respiratory tract infections | Package labeling: ALT/AST >5× and <8× ULN, stop treatment and monitor ALT/AST levels at least every 2 weeks. Once the ALT/AST levels return to pretreatment values, consider reintroduction of the treatment |
Child-Pugh class B or C: avoid use | ALT/AST >8× ULN: discontinue treatment indefinitely | |||
Macitentan [13] | Metabolized primarily by oxidative depropylation of the sulfamide to form the pharmacologically active metabolite. This reaction is dependent on CYP3A4 (major) and CYP2C19 (minor) | No adjustment necessary | Anemia, nasopharyngitis, pharyngitis, bronchitis, headache, influenza, and urinary tract infection | Package labeling: if clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin >2× ULN, or by clinical symptoms of hepatotoxicity, discontinue macitentan. Consider reinitiation when hepatic enzyme levels normalize in patients who have not experienced clinical symptoms of hepatotoxicity |
Soluble guanylate cyclase stimulator
| ||||
Riociguat [19] | Metabolized by CYP1A1, CYP3A, CYP2C8 and CYP2J2. Formation of the major active metabolite, M1, is catalyzed by CYP1A1; M1 is further metabolized to the inactive N-glucuronide. | Child-Pugh class A or B: no dosage adjustment required. Child-Pugh class B or C: no data available | Hypotension, bleeding or other side effects (headache, dizziness, dyspepsia/gastritis, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation) | Hold or reduce dose if patient presents with significant acute liver injury and hypotension |
Intravenous prostacyclin therapy
| ||||
Rapid metabolism via hydrolysis at neutral pH in blood (major), also subject to enzymatic degradation (minor); two minimally active metabolites (one from hydrolysis, one from enzymatic degradation) | No adjustment necessary; if initiating therapy, consider starting at the low end of the dosing range and titrating slowly | Possible hypotension or side effects (headache, jaw pain, flushing) | Probably safe for use in patients with liver dysfunction; consider dosage reduction if patient is hypotensive and is experiencing increased side effects (flushing, headache, jaw pain); do not abruptly discontinue therapy | |
Treprostinil [41] | Hepatic metabolism via CYP2C8 (major) and via oxidation and glucuronidation (minor) | Mild to moderate hepatic insufficiency: initial dose should be decreased to 0.625 ng/kg/minute ideal body weight; cautious dosage increase | Hypotension or side effects (headache, jaw pain, flushing) | Exposure is increased in patients with hepatic insufficiency; if patient presents with acute liver injury and signs of increased drug exposure (hypotension, headache, flushing, jaw pain, and so forth), cautiously and gradually decrease dosage until symptoms subside. Do not abruptly discontinue therapy. One reasonable approach is to decrease the treprostinil dose by 10% every 3 hours until symptoms improve |
Severe hepatic insufficiency: no studies performed | ||||
Inhaled vasodilators
| ||||
Nitric oxide, inhaled [42] | Nonhepatic elimination | No dosage adjustments recommended/required | Methemoglobin | Probably safe to use in patients with hepatic dysfunction |
Treprostinil, inhaled [21] | Hepatic metabolism via CYP2C8 (major) and via oxidation and glucuronidation (minor) | Mild-moderate hepatic impairment: up-titrate slowly when initiating. Severe hepatic insufficiency: no studies performed | Hypotension or worsening of side effects (headache, jaw pain, flushing) | Exposure is increased in patients with hepatic insufficiency; if patient presents with acute liver injury and signs of increased drug exposure (hypotension, headache, flushing, jaw pain, and so forth), increase dosing interval and/or decrease inhalations per treatment until symptoms subside |
Iloprost, inhaled [20] | Hepatic metabolism via β-oxidation (major) and cytochrome P450 (minor); major metabolite is inactive | Child-Pugh class B or C: consider increasing the dosing interval (for example, 3 to 4 hours between doses depending on the patient’s response at the end of the dose interval) | Hypotension/syncope, headache, flushing, ALP/GGT increased, flu-like symptoms, hemoptysis, muscle pain/cramping | Exposure is increased in patients with hepatic insufficiency; if patient presents with acute liver injury and signs of increased drug exposure (hypotension, headache, jaw pain, and so forth), consider increasing the dosing interval until symptoms subside |