Designing drug regimens for special intensive care unit populations

Table 1 Results of search strategies for randomized controlled trials

	Number of citations
MEDLINE
Initial search strategy as described in text	5316
Search strategy limited to “clinical trial” and “humans”	726
Of the 725 citations, the number of RCTs with clinically relevant endpoints	0
MEDLINE
Focused search strategy as described in text	2586
Search strategy limited to “clinical trial” and “human”	176
Of the 176 citations, the number of RCTs with clinically relevant endpoints	0
EMBASE
Initial search strategy as described in text limited to terms indexed as major focus	1898
Search strategy limited to “human” or “clinical trial”	1431
Search strategy limited to “article”	870
Of the 871 citations, the number of RCTs with clinically relevant endpoints	0

RCT: Randomized controlled trial.

Table 2 Changes in body composition during intensive care units stay that may affect drug disposition

Lean vs adipose tissue changes during more prolonged stay

Loss of lean tissue

Gain of adipose tissue

Distribution of adipose tissue (e.g., subcutaneous vs visceral)

Gains or losses of total body water throughout stay

Distribution of retained fluid (e.g., intracellular vs extracellular, interstitial vs intravascular)

Reprinted with permission from Erstad[15]. Copyright © by John Wiley Sons, Inc. Reprinted by permission of John Wiley & Sons, Inc.

Table 3 Weight descriptors commonly used in adult patients in the clinical setting

Ideal body weight (IBW)

IBW in kg for men = 50 kg + 2.3 kg for each inch in height over 60 inches

IBW in kg for women = 45.5 kg + 2.3 kg for each inch in height over 60 inches

Adjusted body weight (ABWadj)

ABWadj in kg = IBW + 0.4 (actual weight - IBW)

Lean body weight (LBW)

LBW (men) = (1.10 × weight in kg) – {120 × [(weight in kg)/(height in cm)]2}

LBW (women) = (1.07 × weight in kg) – {148 × [(weight in kg)/(height in cm)]2}

Body mass index (BMI)

BMI = actual body weight (ABW) in kg divided by (height in m)2

Body surface area (BSA) in m2

BSA = square root [(height in cm × ABW in kg)/3600]

Various methods have been used for estimation - inclusion in this table should not be interpreted as support for a particular method. Reprinted with permission from Erstad[15]. Copyright © by John Wiley Sons, Inc. Reprinted by permission of John Wiley & Sons, Inc.

Table 4 Estimates and measurements of size descriptors such as height and weight

Strive for consistency and standardization within and between all healthcare professionals and staff involved in size descriptor estimates and measurements. Examples include:

Method of estimates including formulas and equations used for calculations

Instruments used for measurement and how utilized (e.g., clothes off or on for weight recordings)

Recording and use of units of estimates and measurements (e.g., centimeters vs inches, pounds vs kilograms)

Terminology related to size descriptors (e.g., ideal weight, adjusted weight)

Ensure proper communication and documentation of method (e.g., patient vs provider, estimate vs measurement) used to obtain estimates and measurements of size descriptors

Have ongoing education with evaluation of all personnel involved in the determination and documentation of estimates and measurements

Have periodic evaluation of compliance by area (e.g., ICU vs emergency department)

Ensure that age-appropriate instruments are available and have regularly scheduled calibration

Use technology (e.g., automated infusion devices, dosing calculators) when available to reduce chance of medication errors

Reprinted with permission from Erstad[15]. Copyright © by John Wiley Sons, Inc. Reprinted by permission of John Wiley & Sons, Inc. ICU: Intensive care units.

Table 5 Pharmacokinetic considerations in the critically ill patient

Data from pharmacokinetic studies are no substitute for clinical monitoring of the individual patient’s response to therapy

Pharmacokinetic parameters derived from studies involving normal volunteers or less severely ill patients are not directly applicable to the critically ill patient

Average parameters for volume of distribution and clearance are larger and have much greater variability in critically ill patients compared with less severely ill patients

The duration of action of single or isolated IV doses of more lipophilic drugs used in the ICU is a function more of distribution than of clearance

The values for volume of distribution and clearance frequently change from baseline with prolonged drug administration because of factors such as accumulation or altered elimination

For drugs with active metabolites, the pharmacokinetics of the metabolites as well as the parent compound must be considered

Drug absorption is important not only with oral or enteral administration but also with intramuscular and subcutaneous injections

Reprinted with permission from Erstad[56]. ICU: Intensive care units.

Table 6 Assessment of possible dose proportionality in studies with obese subjects¹

Did the study involve a comparator group of normal weight subjects of similar demographics (e.g., age, height, gender) and co-morbidities as the obese subjects?

Did the values of pharmacokinetic parameters unadjusted for bodyweight (e.g., volume of distribution in mL and clearance in mL/min) increase proportionally to weight in the obese vs the normal-weight subjects?

Were the values of pharmacokinetic parameters adjusted for actual bodyweight (e.g., volume of distribution in mL/kg and clearance in mL/min per kilogram) similar in the obese and normal-weight subjects?

Did the values of pharmacokinetic parameters adjusted for ideal bodyweight (e.g., volume of distribution in mL/kg and clearance in mL/min per kilogram) increase proportionally to weight in the obese vs the normal-weight subjects?

Was the calculated half-life based on the pharmacokinetic parameters similar in the obese and normal-weight subjects?

When actual bodyweight was used in weight-based dosing protocols were the therapeutic effects and dose-related adverse drug events similar in the obese and normal-weight subjects?

¹If the answers to all of these questions are yes, the data suggests that dose proportionality is present, although this does not necessarily mean that actual bodyweight should be used in weight-based dosing protocols. Reprinted with permission from Erstad[15]. Copyright © by John Wiley Sons, Inc. Reprinted by permission of John Wiley & Sons, Inc.

Table 7 Considerations with therapeutic drug monitoring

Blood concentration measurements are not available for the majority of drugs used in critically ill patients

So-called therapeutic ranges for therapeutic drug monitoring (TDM) are typically derived from studies involving small numbers of patients

Most therapeutic ranges are based on steady-state drug concentrations, so non–steady-state concentrations can be very difficult to interpret (and often meaningless)

Disease states that affect a drug’s volume of distribution or clearance often negate the presumption of steady-state conditions necessary for proper interpretation of concentrations

The minimum and maximum concentrations used to define a therapeutic range are often quite arbitrary and not necessarily applicable to a specific patient

The free or unbound form of a drug is the active form, but the total drug concentration is most commonly measured by clinical laboratories

Total drug concentrations for a drug with high protein binding (e.g., > 90%) can be difficult to interpret when protein concentrations are decreased or when other drugs or diseases displace drug

Clinical response, not a TDM measurement, should be the primary driver of dosing decisions

The administration and timing of drug doses prior to TDM measurement should be verified, not presumed, because these affect the proper interpretation of the measurement

TDM is most useful when clinical indicators are misleading or not available or when the clinical indicator is a problem that the clinician is trying to prevent (e.g., aminoglycoside nephrotoxicity)

Unnecessary TDM should be avoided (e.g., ordering daily measurements of drug concentrations for a drug with a long half-life) because it may lead to inappropriate changes and unnecessary TDM costs

Reprinted with permission from Erstad[56].

Table 8 Conceptual framework for dosing medications in obese patients¹

Step 1

Evaluate the clinical investigations involving the medication to determine the degree of obesity in the patients under study and the weight descriptor used for dosing, which is usually actual body weight (ABW) in studies leading to medication approval. Determine if the patient under consideration appears to fit the profile of the patients in the study; be particularly cautious if the patient is extremely obese. If the patient appears to fit the profile of the patients in the studies, use the weight descriptor. If not, proceed to Step 2

↓

Step 2

If the patient does not fit the profile of the patients in the clinical investigations, search the literature for pharmacokinetic studies involving the medication in obese patients. Assess whether the pharmacokinetic parameters of the medication appear to increase proportionately with increasing weight suggesting that use of ABW may be appropriate. If the patient appears to fit the profile of the patients in the studies, consider using the weight descriptor and proceed to Step 5. If not, proceed to Step 3

↓

Step 3

If the patient does not fit the profile of the patients in the clinical investigations and if no pharmacokinetic studies involving the specific medication in obese patients are available, evaluate the literature for dosing studies in obese patients with medications that have similar physicochemical and pharmacokinetic parameters (e.g., medications in the same class). If the patient appears to fit the profile of the patients in the studies, consider using the weight descriptor and proceed to Step 5. If not, proceed to Step 4

↓

Step 4

If no relevant studies can be found, and particularly if the patient is extremely obese, assess whether an alternative medication (where more is known about dosing in obese patients) might be appropriate. If there is no equivalent or better medication option available, proceed to Step 5

↓

Step 5

Assess the benefits and risks of using ABW for dosing using step 5a for weight-based dosing or 5b for non-weight based dosing

Step 5a

If weight-based dosing (e.g., mg/kg) is being used, assess whether the potential benefits of using ABW (e.g., need to reach therapeutic range quickly) are likely to exceed the potential risks of over-dosing. If the patient under consideration is substantially heavier than the patients in the investigations or if no studies are available, assess whether a lean body weight or adjusted body weight equation might be preferable, especially in medications with a narrow therapeutic range and small (e.g., < 0.2 L/kg) to moderate (e.g., 0.2 to 1 L/kg) volumes of distribution that are cleared primarily by glomerular filtration

Step 5b

If non-weight-based dosing (e.g., mg/dose) is being used, assess whether the potential benefits of using a larger dose are likely to exceed the potential risks of over-dosing if the patient under consideration is substantially heavier than the patients who were enrolled in the clinical investigations involving the medication, and if the medication has a narrow therapeutic range and a moderate (0.2 to 1 L/kg) to large (> 1 L/kg) volume of distribution

¹Should always take into account potential co-morbidity confounders such as renal or liver dysfunction when determining dosing regimens. Reprinted with permission from Erstad[57].

Table 9 Implications of medications for the pregnant critically ill patient

Indication/class	Specific drug	FDA3	Comments1	Indication/class	Specific drug	FDA3	Comments1
Sedative	Propofol	B		Anticoagulant	Enoxaparin	B
	Midazolam	D			Heparin	C
	Lorazepam	D	Risk (1st and 3rd trimesters)		Fondaparinux	B
	Dexmedetomidine	C			Argatroban	B
Analgesic	Morphine	C	Risk (3rd trimester)	Corticosteroid	Methylprednisolone	C
	Fentanyl	C	Risk (3rd trimester)		Hydrocortisone	C	Data suggest risk
	Hydromorphone	C	Risk (3rd trimester)	Antifungal/antiviral	Voriconazole	D
Delirium	Quetiapine	C	Risk (1st and 3rd trimesters)		Fluconazole	D	Data suggest risk if > 400 mg/d
	Haloperidol	C			Micafungin	C
Pulmonary hypertension	Epoprostenol	B			Amphotericin	B
	Treprostinil	B			Acyclovir	B
	Iloprost	C		Antibiotic	Azithromycin	B
Bronchodilator	Tiotropium	C			Aztreonam	B
	Ipratropium	B			Cefazolin	B
	Albuterol	B			Cefepime	B
	Levalbuterol	C			Cefoxitin	B
Vasoactive	Epinephrine	C	Data suggest risk		Ceftriaxone	B
	Norepinephrine	C	Data suggest risk		Ciprofloxacin	C	Data suggest low risk
	Vasopressin	C			Clindamycin	B
	Phenylephrine	C	Data suggest risk		Linezolid	C
	Dopamine	C			Meropenem	B
	Dobutamine	B			Metronidazole	B	Data suggest low risk
	Milrinone	C			Moxifloxacin	C	Data suggest low risk
Antiarrhythmic	Diltiazem	C	Data suggest low risk		Piperacillin/tazobactam	B
	Amiodarone	D	Data suggest risk		Vancomycin	C
	Digoxin	C		Anti-seizure2	Levetiracetam	C
Antihypertensive	Labetalol	C	Data suggest low risk		Phenytoin	D
	Esmolol	C		Paralytic	Rocuronium	C
	Hydralazine	C	Risk (3rd trimester)		Cisatracurium	B
	Magnesium sulfate	D			Vecuronium	C
	Nitroglycerin	C	Data suggest low risk		Succinylcholine	C
	Sodium nitroprusside	C	Data suggest risk
	ACE-inhibitors	D	Data suggest risk (2nd and 3rd trimesters)
Diuretic	Furosemide	C	Data suggest low risk
	Mannitol	C
GI/antiemetic	Pantoprazole	B	Data suggest low risk
	Famotidine	B
	Ondansetron	B
	Metoclopramide	B
	Erythromycin (non-estolate)	B

¹Human data to suggest risk based on data from Briggs et al[23];

²Pregnant women exposed to AEDs should register with the North American Antiepileptic Drug Pregnancy Registry (888-233-2334);

³Refers to FDA pregnancy rating category. FDA: Food and Drug Administration; ACE: Angiotensin converting enzyme.

Table 10 Drug dosing considerations in adult patients receiving extracorporeal membrane oxygenation

Drug dosing recommendations for an adult on ECMO are unlikely to be evidenced-based

Data from neonatal case reports, case series or studies may not apply to adults

Data from one drug may not be applicable to another even from the same class

Drug regimen recommendations in critical care guidelines may not apply to patients on ECMO

Organ dysfunction apart from the lung and heart complicate interpretation of literature

The contribution of distinct physicochemical properties of drugs to sequestration is unclear

Hydrophilicity or lipophilicity appear to be important factors affecting pharmacokinetics

The therapeutic actions of drugs are not consistently predictable by pharmacokinetics

The design and properties of the equipment change over time with implications for dosing

The priming solution such as blood or blood-derived products may affect dosing

ECMO: Extracorporeal membrane oxygenation.

Table 11 Pharmacokinetic and physicochemical properties of drugs commonly used in the intensive care units¹

Indication/class	Specific drug	LogP	Pb (%)	Vd (L/kg)
Sedative
	Propofol	4.16	98	60
	Midazolam	3.33	97	2
	Lorazepam	3.53	91	1.3
	Dexmedetomidine	3.39	94	1.3
Analgesic
	Morphine	0.9	35	3
	Fentanyl	3.82	83	5
	Hydromorphone	1.62	20	1.2
Delirium
	Quetiapine	2.81	83	10
	Haloperidol	3.66	92	18
Antiarrhythmic
	Diltiazem	2.37	80	5
	Amiodarone	7.64	98	70
	Digoxin	2.37	25	6
Antihypertensive
	Labetalol	1.89	50	5
	Esmolol	1.82	55	3
	Hydralazine	0.75	87	4
GI/antiemetic
	Pantoprazole	2.18	98	0.15
	Famotidine	-2	18	1.2
	Ondansetron	2.35	73	2
	Metoclopramide	1.4	30	4.4
	Erythromycin	2.6	85	0.6
Anticoagulant
	Enoxaparin	-8.3	80	0.07
	Heparin	NA	NA	0.05
	Fondaparinux	-10	94	0.1
	Argatroban	-0.97	54	0.17
Corticosteroid
	Methylprednisolone	1.56	78	1.1
	Hydrocortisone	1.28	95	0.5
Antifungal/antiviral
	Voriconazole	1.82	58	3
	Fluconazole	0.56	11	0.8
	Micafungin	-6.3	99	0.39
	Amphotericin	-2.3	95	1.8
	Acyclovir	-1	9-33	0.6
Antibiotic
	Azithromycin	2.44	51	0.44
	Aztreonam	-3.1	56	0.17
	Cefazolin	-1.5	80	0.14
	Cefepime	-4.3	20	0.23
	Cefoxitin	0.29	75	0.26
	Ceftriaxone	-1.8	95	0.14
	Ciprofloxacin	-0.81	35	2.5
	Clindamycin	1.04	93	2.5
	Linezolid	0.64	31	0.64
	Meropenem	-4.4	2	0.36
	Metronidazole	-0.46	25	1
	Moxifloxacin	-0.5	50	2
	Piperacillin/tazobactam	-0.26		0.1
	Vancomycin	-3.1	55	0.7
Anti-seizure
	Levetiracetam	-0.59	8	0.6
	Phenytoin	2.15	90	0.7

¹LogP is the octanol-water partition coefficient and is expressed as the ratio of the solubility of a compound in octanol (non-polar solvent) to its solubility in water (polar solvent). Some of the data from this table (particularly the log P values) were obtained from http://www.drugbank.ca. NA: Not applicable.