PLoS MEDICINE

Lethal Injection for Execution:
Chemical Asphyxiation?
Teresa A. Zimmers1,2, Jonathan Sheldon3, David A. Lubarsky4,5, Francisco Lo´pez-Mun˜oz6, Linda Waterman7,
Richard Weisman8, Leonidas G. Koniaris1,2*
1 Dewitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America, 2 Department of Cell Biology and
Anatomy, University of Miami Miller School of Medicine, Miami, Florida, United States of America, 3 Devine, Connell & Sheldon, P.L.C., Fairfax, Virginia, United States of
America, 4 Department of Anesthesiology, Perioperative Medicine, and Pain Management, University of Miami Miller School of Medicine, Miami, Florida, United States of
America, 5 Department of Management, University of Miami School of Business, Miami, Florida, United States of America, 6 Department of Pharmacology, University of
Alcala´, Madrid, Spain, 7 Department of Comparative Medicine and Pathology, University of Miami Miller School of Medicine, Miami, Florida, United States of America,
8 Florida Poison Center–Miami, University of Miami Miller School of Medicine, Miami, Florida, United States of America
Funding: The authors received no
specific funding for this study.
Competing Interests: JPS practices
capital defense. DAL has been a paid
expert consultant in death penalty
litigation. The other authors have no
conflicts to disclose.
Academic Editor: Clifford J. Woolf,
Harvard Medical School, United
States of America
Citation: Zimmers TA, Sheldon JP,
Lubarsky DA, Lo´pez-Mun˜oz F,
Waterman L, et al. (2007) Lethal
injection for execution: Chemical
asphyxiation? PLoS Med 4(4): e156.
doi:10.1371/journal.pmed.0040156
Received: September 27, 2006
Accepted: March 2, 2007
Published: April 24, 2007
Copyright: Ó 2007 Zimmers et al.
This is an open-access article
distributed under the terms of the
Creative Commons Attribution
License, which permits unrestricted
use, distribution, and reproduction
in any medium, provided the
original author and source are
credited.
Abbreviations: ECG,
electrocardiogram; HED, human
equivalent dose; IV, intravenous
*To whom correspondence should
be addressed. E-mail:LKoniaris@med.
miami.edu

ABSTRACT
Background
Lethal injection for execution was conceived as a comparatively humane alternative to
electrocution or cyanide gas. The current protocols are based on one improvised by a medical
examiner and an anesthesiologist in Oklahoma and are practiced on an ad hoc basis at the
discretion of prison personnel. Each drug used, the ultrashort-acting barbiturate thiopental, the
neuromuscular blocker pancuronium bromide, and the electrolyte potassium chloride, was
expected to be lethal alone, while the combination was intended to produce anesthesia then
death due to respiratory and cardiac arrest. We sought to determine whether the current drug
regimen results in death in the manner intended.

Methods and Findings
We analyzed data from two US states that release information on executions, North Carolina
and California, as well as the published clinical, laboratory, and veterinary animal experience.
Execution outcomes from North Carolina and California together with interspecies dosage
scaling of thiopental effects suggest that in the current practice of lethal injection, thiopental
might not be fatal and might be insufficient to induce surgical anesthesia for the duration of
the execution. Furthermore, evidence from North Carolina, California, and Virginia indicates
that potassium chloride in lethal injection does not reliably induce cardiac arrest.

Conclusions
We were able to analyze only a limited number of executions. However, our findings suggest
that current lethal injection protocols may not reliably effect death through the mechanisms
intended, indicating a failure of design and implementation. If thiopental and potassium
chloride fail to cause anesthesia and cardiac arrest, potentially aware inmates could die through
pancuronium-induced asphyxiation. Thus the conventional view of lethal injection leading to
an invariably peaceful and painless death is questionable.
The Editors’ Summary of this article follows the references.

PLoS Medicine | www.plosmedicine.org

0646

April 2007 | Volume 4 | Issue 4 | e156

Lethal Injection for Execution

Introduction

The North Carolina warden pronounces death after a flat line
is displayed on the electrocardiogram (ECG) monitor for 5
min, thus time to death was calculated from start time to
pronouncement of death less 5 min. Dosages were calculated
from postmortem body weights taken from Reports of
Investigation by the North Carolina Office of the Chief
Medical Examiner. Information regarding the California
protocol and execution logs and Florida and Virginia
executions were obtained through available court documents
[9,10,11]. Data are expressed as mean 6 standard deviation.
One-way ANOVA with Tukey’s multiple comparison test was
used for statistical analysis.

In the United States, lethal injection can be imposed in 37
states and by the federal government and military. The origin
of the lethal injection protocol can be traced to legislators in
Oklahoma searching for a less expensive and potentially more
humane alternative to the electric chair [1]. Both the state
medical examiner and a chairman of anesthesiology appear
to have been consulted in writing of the statute. The medical
examiner has since indicated that no research went into his
choice of drugs—thiopental, pancuronium bromide, and
potassium chloride—but rather he was guided by his own
experience as a patient [2]. His expectation was that the
inmate would be adequately anesthetized, and that although
each individual drug would be lethal in the dosage specified,
the combination would provide redundancy. The anesthesiologist’s input relating to thiopental was written into law as
‘‘the punishment of death must be inflicted by continuous,
intravenous administration of a lethal quantity of an ultrashort-acting barbiturate in combination with a chemical
paralytic agent’’ [3], although in practice Oklahoma uses
bolus dosing of all three drugs [4,5]. Texas, the first state to
execute a prisoner by lethal injection, and subsequently other
jurisdictions, copied Oklahoma’s protocol without any additional medical consultation [1].
Although executioners invariably achieve death, the mechanisms of death and the adequacy of anesthesia are unclear.
Used independently in sufficiently high doses, thiopental can
induce death by respiratory arrest and/or circulatory depression, pancuronium bromide by muscle paralysis and respiratory arrest, and potassium chloride by cardiac arrest. When
used together, death might be achieved by a combination of
respiratory arrest and cardiac arrest due to one or more of
the drugs used. Because thiopental has no analgesic effects (in
fact, it can be antianalgesic) [6], and because pancuronium
would prevent movement in response to the sensations of
suffocation and potassium-induced burning, a continuous
surgical plane of anesthesia is necessary to prevent extreme
suffering in lethal injection.
Recently we reported that in most US executions, executioners have no anesthesia training, drugs are administered
remotely with no monitoring for anesthesia, data are not
recorded, and no peer review is done [7]. We suggested that
such inherent procedural problems might lead to insufficient
anesthesia in executions, an assertion supported by low
postmortem blood thiopental levels and eyewitness accounts
of problematic executions. Because of a current lack of data
and reports of problems with lethal injection for executions,
we sought to evaluate the three-drug protocol for its efficacy
in producing a rapid death with minimal likelihood of pain
and suffering.

Results
Data from North Carolina Executions
Three lethal injection protocols have been used in North
Carolina from the first execution in 1984 to the most recent
at the time of this writing in August 2006 (Figure 1A). The
initial use of serial, intravenous (IV) injections of 3 g of
thiopental and 40 mg of pancuronium bromide (referred to
here as ‘‘Protocol A,’’ n ¼ 8, Figure 1A) was superseded by
Protocol B in 1998. Protocol B consisted of serial injections of
1.5 g of thiopental, 80 mEq of potassium chloride, 40 mg of
pancuronium bromide, 80 mEq of potassium chloride, and
finally 1.5 g of thiopental (n ¼ 21) [1,12]. After criticism from
expert witnesses [13], in 2004 the injection order was changed
to the current protocol of serial injections of 3 g of
thiopental, 40 mg of pancuronium bromide, and 160 mEq
of potassium chloride (Protocol C, n ¼ 11) [14]. Each injection
is performed in rapid succession with intermittent saline
flushes to avoid drug precipitation. Until the last two
executions in 2007, no assessment or monitoring of anesthesia was performed.
According to the North Carolina Department of Corrections, once the ECG monitor displays a flat line for 5 min, the
warden declares death and a physician certifies that death has
occurred [7, 12]. Execution start times and declaration times
were available for 33 of the 42 lethal injections conducted in
North Carolina (Figure 1B). Mean times to death were 9.88 6
3.87 min for Protocol A, 13.47 6 4.88 min for Protocol B, and
9.00 6 3.71 min for Protocol C. The mean time to death for
Protocol B was significantly longer than for Protocol C (p ,
0.05, Tukey-Kramer test after one-way ANOVA). No other
differences were statistically significant. These data indicate
that the five-dose regimen of Protocol B slightly prolonged
time to death, but more importantly, they indicate that the
addition of potassium chloride did not hasten death overall.
In contrast to clinical use of these same drugs, jurisdictions
invariably specify mass quantities for injection rather than
dosing by body weight. We sought to determine the actual
doses used in executions using postmortem body weights
recorded by the Office of the Medical Examiner. North
Carolina injects 3 g of thiopental; however, in Protocol B
inmates were given half the thiopental at the end, once all
painful stimuli were administered and death should have
been achieved. Thus we considered only the first 1.5 g for
Protocol B. Overall the median thiopental dose was 20.3 mg/
kg (range 11.2–44 mg/kg, n ¼ 40) (Figure 1C). Virtually all of
the lowest doses were under Protocol B, although four very
large individuals executed under Protocols A and C received
less than the median dose. Eyewitness reports of inmate

Methods
North Carolina lethal injection protocols were determined
from Department of Corrections drug procurement records
and testimony of prison personnel participating in the
process. Times to death were determined from North
Carolina Department of Corrections documents including
the Web site [8], official statements, and corroborating news
and eyewitness reports. Start times were available for 33
executions, of which 19 could be independently confirmed.
PLoS Medicine | www.plosmedicine.org

0647

April 2007 | Volume 4 | Issue 4 | e156

Lethal Injection for Execution

thiopental, 100 mg of pancuronium bromide, and 100 mEq of
potassium chloride [9]. California Department of Corrections
form 226A, ‘‘Lethal Injection—Execution Record,’’ consists of
a table listing ‘‘operations,’’ including injection of each drug,
cessation of respiration, flatlining of the cardiac monitor, and
pronouncement of death, with columns for time, heart rate,
and respiration rate. Such execution records were available
for nine of the 11 lethal injections performed in San Quentin
California State Prison from 1996 to 2006 [9,10]. One record
was incomplete and contradictory and is not reported here.
In the remaining eight executions, respiration rate ceased
from 1 min (inmate WB1966) to 9 min (CA2006) after the
injection of thiopental (Figure 2). Cessation of respiration
was noted coincident with (WB1966, SW2005, CA2006) or up
to 3 min after (SA2002) injection of pancuronium bromide.
Flatlining of the cardiac monitor occurred 2 min (DR2000) to
8 min (JS1999) after the last injection of potassium chloride.
The records indicate that a second dose of potassium
chloride was used in the execution of SA2002, and the
California warden has said that additional doses were used in
two other executions, one being CA2006 and the other
unknown [16]. Eyewitness reports document ‘‘sudden and
extreme’’ convulsive movements 3–4 min into the execution
of MB1999 [17] and more than 30 heaving, convulsive
movements of the chest and abdomen of SA2002 [18].

Discussion
Most US executions are beset by procedural problems that
could lead to insufficient anesthesia in executions. This
hypothesis has been supported by findings of low postmortem
blood thiopental levels and eyewitness accounts of problematic executions. Herein we report evidence that the design of
the drug scheme itself is flawed. Thiopental does not
predictably induce respiratory arrest, nor does potassium
chloride always induce cardiac arrest. Furthermore, on the
basis of execution data and clinical, veterinary, and laboratory animal studies, we posit that the specified quantity of
thiopental may not provide surgical anesthesia for the
duration of the execution. Thus some inmates may experience the sensations of pancuronium-induced paralysis and
respiratory arrest.
In the United States and Europe, techniques of animal
euthanasia for clinical, laboratory, and agricultural applications are rigorously evaluated and governed by professional,
institutional, and regulatory oversight. In university and
laboratory settings, local oversight bodies known as Animal
Care and Use Committees typically follow the American
Veterinary Medical Association’s guidelines on euthanasia,
which consider all aspects of euthanasia methods, including
drugs, tools, and expertise of personnel in order to minimize
pain and distress to the animal. Under those guidelines, lethal
injections of companion or laboratory animals are limited to
injection by qualified personnel of certain clinically tested,
Food and Drug Administration–approved anesthetics or
euthanasics, while monitoring for awareness.
In stark contrast to animal euthanasia, lethal injection for
judicial execution was designed and implemented with no
clinical or basic research whatsoever. To our knowledge, no
ethical or oversight groups have ever evaluated the protocols
and outcomes in lethal injection. Furthermore, there are no
published clinical or experimental data regarding the safety

Figure 1. Lethal Injection Executions in North Carolina
(A) Schematic depicting quantity and order of drug administration in the
three protocols.
(B) Time to death by protocol, calculated as the interval from execution
start time to declaration of death, minus 5 min (see Methods).
(C) Actual dose of thiopental by body weight (not available for all
inmates). In Protocol B, 1.5 g of thiopental was given after the
pancuronium bromide and potassium chloride, once painful stimuli
had been administered and death should have occurred; accordingly,
only the first 1.5 g dose is plotted.
doi:10.1371/journal.pmed.0040156.g001

movement including convulsions and attempts to sit up in
four executions [15] did not cluster in the lowest doses, but
rather occurred at doses of 17.1, 18.9, 19.6, and 21 mg/kg, all
performed under Protocol B. Calculated median doses of
pancuronium bromide and potassium chloride were 0.46 mg/
kg (range 0.28–0.46 mg/kg) and 1.83 mEq/kg (range 1.11–2.35
mEq/kg), respectively.

Data from California Executions
Executions in California provided a second insight into the
methodologies and outcomes in lethal injections. The public
version of the California protocol specifies injection of 5 g of
PLoS Medicine | www.plosmedicine.org

0648

April 2007 | Volume 4 | Issue 4 | e156

Lethal Injection for Execution

however, suggest that thiopental alone might not be lethal.
First, extrapolating from clinical use, the lowest dosages used
in some jurisdictions would not be expected to kill.
Calculated dosages in North Carolina executions using 3 g
of thiopental ranged from 10 to 45 mg/kg. Assuming inmates
are roughly the same size across jurisdictions, the dose range
would be 17–75 mg/kg in California, where 5 g of thiopental is
used, and 6.6–30 mg/kg in Virginia and other jurisdictions,
which use 2 g. Thus, at the lowest doses, thiopental would be
given near the upper range of that recommended for clinical
induction of anesthesia (3–6.6 mg/kg)—clearly not a dose
designed to be fatal [20]. Second, the calculated doses used
across lethal injections are only 0.1–2 times the LD50 (dose
required to kill 50% of the tested population) of thiopental in
dogs (37 mg/kg), rabbits (35 mg/kg), rats (57.8 mg/kg), and mice
(91.4 mg/kg) [21, 22]. Third, intravenous delivery of thiopental
alone is not recommended by The Netherlands Euthanasics
Task Force, which concluded ‘‘it is not possible to administer
so much of it that a lethal effect is guaranteed’’ [23], even in
their population of profoundly ill patients.
The most compelling evidence that even 5 g of thiopental
alone may not be lethal, however, is that some California
inmates continued to breathe for up to 9 min after thiopental
was injected. This observation directly contradicts testimony
of that state’s expert witness, who asserted that ‘‘this dose of
thiopental sodium will cause virtually all persons to stop
breathing within a minute of drug administration’’ and that
‘‘virtually every person given 5 grams of thiopental sodium
will have stopped breathing prior to the administration of the
pancuronium bromide’’ [24]. The witness has made identical
statements regarding 3 g of thiopental [14]. Indeed, the
clinical literature is replete with examples of patients
experiencing respiratory failure after even low doses of
thiopental [25]. Others, however, experience merely transient, nonfatal apnea. Of course, for inmates who did not stop
breathing with thiopental alone, it is impossible to know
whether the thiopental solution was correctly mixed, whether
the entire dose was administered intravenously, or whether
the apparent resistance was due to bolus dosing or individual
variation. It remains possible, however, that bolus dosing of 5
g of thiopental alone might not be fatal in all persons. Indeed,
nonhuman primates given as much as 60 mg/kg (the mass
equivalent of 6 g for a 100 kg man) experienced prolonged
sleep, but ultimately recovered [26].
If thiopental does not reliably kill the inmates, then
perhaps death is effected by potassium chloride. Rapid
intravenous or intracardiac administration of 1–2 mmol/kg
potassium chloride under general anesthesia is considered
acceptable for euthanasia of large animal species; thus the
1.11–2.35 mmol/kg doses given in North Carolina’s lethal
injections ought to be fatal. If potassium chloride contributes
to death through cardiotoxicity, however, cardiac activity
ought to cease more quickly when potassium is used than
when it is not. Indeed, such is the principle behind the animal
euthanasia agent, Beuthanasia-D Special, in which the
cardiotoxic effects of phenytoin synergize with the central
nervous system–depressive effects of pentobarbital, accelerating death over pentobarbital alone [27]. In contrast, our
analysis shows that use of potassium chloride in North
Carolina’s Protocol C did not hasten death (defined as
flatlining of the ECG) over Protocol A, which used thiopental
and pancuronium alone. Moreover, in California executions,

Figure 2. Lethal Injection Executions in California
Depicted are duration of respiration and heart rate after initiation of the
thiopental injection at time 0. Injection of pancuronium bromide is
indicated by the grey arrow, potassium chloride by the black arrow. Note
that additional injections of potassium chloride in SA2002 and of
pancuronium bromide in WB1996. SW2005 was noted to be breathing 3
min after thiopental, but not at the time of pancuronium bromide
injection; the exact time respiration ceased was not recorded. DR2000
was noted to have chest movements two minutes after respiration was
noted to have ceased. *A second dose of potassium chloride were
administered to CA2006, but not noted on the log. A third, unidentified
inmate was also given a second dose of potassium chloride, according to
the warden (see text).
doi:10.1371/journal.pmed.0040156.g002

and efficacy of the three-drug lethal injection protocol. Until
the unprecedented and controversial use of bispectral index
monitoring in the last two North Carolina lethal injections
[19], no monitoring for anesthesia was performed. Given this
paucity of knowledge and documentation, we sought to
evaluate available data in order to determine the efficacy of
the three drug protocol.
The designers of lethal injection intended that each of the
drugs be fatal independently and that the combination
provide redundancy [2]. Moreover, in legal challenges to the
death penalty, the leading expert witness testifying on behalf
of the states routinely asserts that 3 g of thiopental alone is a
lethal dose in almost all cases [14]. The data presented here,
PLoS Medicine | www.plosmedicine.org

0649

April 2007 | Volume 4 | Issue 4 | e156

Lethal Injection for Execution

Table 1. Reported Duration of Sleep or Anesthesia after Bolus IV Injections of Thiopental in Experimental Animals
Species

Dose
(mg/kg)

Mouse
Rat

30
20
25
18
22
20
21
22
10.2
10.9
15
25
20
25
12.7–13.9
13.8–25.0
20
60

Rabbit

Dog

Sheep
Goat
Swine
Cattle
Nonhuman primate

n

32
7
1
10
16
5
5
8
22
4

Mean Duration
of Sleepa (min)
4.7–6.4
4.0–7.0
22.6
9.3–10.5
30.0 6 6.0
0
28
14.8–15.2
10.8
11.4
26
74.4 6 7.1

0

1.8
1.4
8.5
18.3 6 5.10
15
12.0 6 5.20
5.5 6 2.7
32.25 6 14.36

30–45
4
4
4
1

Mean Duration of
Anesthesiab (min)

95

Reference

Calculated HEDc
(mg/kg)

[43]
[43]
[43]
[44]
[44]
[45]
[21]
[44]
[46]
[46]
[47]
[47]
[48]
[49]
[48]
[48]
[46]
[43]

2.4
3.2
4
2.88
3.52
6.4
6.72
7.04
5.51
5.89
8.1
13.5
18.1
22.6
8.8–9.6
12.3–22.4
28.8
16.5

a

From loss to return of righting reflex or voluntary movement.
Typically corneal areflexia.
Human equivalent dose was calculated as HED ¼ animal dose (mg/kg) 3 (animal weight [kg]/human weight [kg])0.33 [35,36].
doi:10.1371/journal.pmed.0040156.t001

b
c

were misplaced and the drugs were delivered subcutaneously
[31].
Executions such as Diaz’s, in which additional drugs were
required, constitute further evidence that the lethal injection
protocols are not adequate to ensure a predictable, painless
death. Court documents and news reports indicate that at
least Virginia [32], California [10], and Florida [31] have
administered additional potassium chloride in multiple
executions when the inmate failed to die as expected. If a
Virginia execution takes too long and if the inmate fails to
die, the protocol indicates that additional pancuronium and
potassium chloride should be injected, although there is no
provision for additional thiopental [32]. In cases such as
Diaz’s, additional drugs may have been required due to
technical problems with delivery, but it remains possible that
in others, the standard drug protocol failed to kill.
Given the uncertainty surrounding the mechanism of death
and low postmortem blood thiopental levels in some
executed inmates [7], one must ask whether adequate
anesthesia is maintained to prevent awareness and suffering.
Medical experts on both sides of the lethal injection debate
have asserted that 3 g of thiopental properly delivered should
reliably result in either death or a long, deep surgical plane of
anesthesia [13,14]. In support of this contention, continuous
or intermittent thiopental administration was formerly used
for surgical procedures lasting many hours. In one study, 3.3–
3.9 g given to patients over 25–50 min resulted in sleep for 4–
5.5 h [33]. Depth and duration of thiopental anesthesia
depends greatly upon dose and rate of administration,
however, and bolus dosing results in significantly different
pharmacokinetics and duration of efficacy than administration of the same quantity of drug at a lower rate [22].
In the modern practice of anesthesia, thiopental is used
solely to induce a few moments of anesthesia prior to
administering additional agents. Anesthesiologists are taught

ECG flatlining was noted from 2 to 9 min after potassium
chloride administration. This observation contrasts sharply
with reports of accidental bolus IV administration of
concentrated potassium chloride solution, in which patients
experienced complete cardiopulmonary arrest almost immediately upon injection [28]. The North Carolina and
California data together suggest that potassium chloride
might not be the lethal agent in lethal injection.
Given that neither thiopental nor potassium chloride can
be construed reliably to be the agent of death in lethal
injection, death in at least some inmates might have been due
to respiratory cessation from the use of pancuronium
bromide. The typical use of 0.06–0.1 mg/kg pancuronium
bromide under balanced anesthesia produces 100% neuromuscular blockade within 4 min, with approximately 100 min
required for 25% recovery [29]. The doses used in North
Carolina were some 3–11 times greater than the typical
intubation dose, and thus would be expected to produce
more rapid paralysis of many hours duration and complete
respiratory arrest [30]. Indeed, pancuronium might have been
the agent of death even in inmates who ceased breathing
coincident with or shortly after injection of pancuronium,
rendering permanent the thiopental-induced apnea. In
addition, because pancuronium bromide is effective even
when delivered subcutaneously or intramuscularly, pancuronium is likely the sole agent of death when IV catheter
misplacement or blowout impairs systemic delivery of the
other two drugs. In such cases death by suffocation would
occur in a paralyzed inmate fully aware of the progressive
suffocation and potassium-induced sensation of burning.
This was likely the experience of Florida inmate Angel Diaz,
whose eyes were open and mouth was moving 24 min into his
execution and who was pronounced dead after 34 min.
Findings of two 30-cm burns over both antecubital fossae
prompted the medical examiner to conclude that the IV lines
PLoS Medicine | www.plosmedicine.org

0650

April 2007 | Volume 4 | Issue 4 | e156

Lethal Injection for Execution

data limited, however, medical literature addressing the
effects of these drugs at high doses and in combination is
nonexistent, emphasizing the failure of lethal injection
practitioners to design and evaluate rigorously a process that
ensures reliable, painless death, even in animals. In consequence, the adequacy of anesthesia and mechanism of death
in the current lethal injection protocol remains conjecture.
Despite such limitations, our analysis of data from more
forthcoming states along with reports of problematic
executions and judicial findings [41] together indicate that
the protocol of lethal injection for execution is deeply flawed.
Technical difficulties are clearly responsible for some mishandled executions, such as Diaz’s. Better training of
execution personnel and altering delivery conditions may
not ‘‘fix’’ the problem [41, 42], however, because the drug
regimen itself is potentially inadequate. Our analysis indicates that as used, thiopental might be insufficient both to
maintain a surgical plane of anesthesia and to predictably
induce death. Consequently, elimination of pancuronium or
both pancuronium and potassium, as has been suggested in
California [41], could result in situations in which inmates
ultimately awaken.
With the growing recognition of flaws in the lethal
injection protocol, 11 states have now suspended the death
penalty, with nine of those seeking resolution of issues
surrounding the process [42]. In California and Florida,
commissions of experts have been charged with evaluating
and refining lethal injection protocols. As deliberations
begin, we suggest that the secrecy surrounding protocol
design and implementation should be broken. The available
data or lack of data should be made public and deliberations
should be open and transparent.

to administer a small test dose while assessing patient
response and the need for additional doses [20]. Such
stepwise administration and evaluation has been the practice
from the first reports of thiopental usage in 1934, due to the
known potential for barbiturate-induced respiratory arrest
[34]. It was early recognized that age, body composition,
health status, anxiety, premedication, and history of substance abuse clearly influence response to thiopental, with
some individuals showing marked resistance to standard
doses [35] and others fatal sensitivity [25]. Thus the historical
and modern clinical use of thiopental results from its
cautious application to prevent respiratory arrest both in
the typical patient and the abnormally susceptible. In
consequence, there is almost no information about duration
of anesthesia following large bolus doses of thiopental in
unpremedicated patients, and there are few living anesthesiologists with clinical experience relevant to lethal injection
protocols.
Unlike in clinical medicine, however, bolus injection of
thiopental is regularly practiced in laboratory animals and
veterinary medicine. Standard texts specify from 6 to 50 mg/
kg thiopental, depending on the species, for 5–10 min of
anesthesia [36], including 18–22 mg/kg for 10–15 min of
anesthesia in dogs, pigs, sheep, and swine [37]. Such dosages
are conservative guidelines based on average responses of
animals in experimental trials (Table 1), with the assumption
that respiration and depth of anesthesia will be assessed in
individual animals prior to onset of the procedure. (In
addition, thiopental is not recommended for painful procedures in animals.) Withholding or administering additional
dosages would compensate for individual variation in
response.
Although species differences complicate pharmacological
comparisons from animals to humans, animal studies are the
basis for virtually all human drug trials. According to FDA
guidelines, toxicity endpoints for drugs administered systemically to animals are typically assumed to scale well across
species when doses are normalized to body surface area (i.e.,
mg/m2) [38]. Calculating the human equivalent dose (HED) as
recommended by the FDA [39] gives a more conservative
estimate of thiopental equivalencies across species than does
using simple mg/kg comparisons (Table 1). Swine in particular
are regarded as an excellent model of human cardiopulmonary and cerebrovascular physiology, with comparable size,
body composition, and brain perfusion rates [40]. Comparing
the HED for thiopental anesthesia in swine to lethal injection
dosages, we conclude that at least some inmates at the lower
end of the thiopental dose range might have experienced
fleeting or no surgical anesthesia, while others at the higher
end of the range might have received doses predicted to
induce more prolonged anesthesia (Table 1). Such a prediction is impossible to evaluate, however, because any
evidence of suffering would be masked by the effects of
pancuronium.
Our study is necessarily limited in scope and interpretations. Given the secrecy surrounding lethal injections, we
were able to analyze only a small fraction of the 891 lethal
injections in the US to date. Indeed, the majority of
executions actually take place in states such as Texas and
Virginia, where the protocols and procedural problems are
likely similar to the ones described, but where the states are
unwilling to provide information [7]. Not only are available
PLoS Medicine | www.plosmedicine.org

Supporting Information
Alternative Language Abstract S1. Translation into Spanish by
Francisco Lo´pez-Mun˜oz
Found at doi:10.1371/journal.pmed.0040156.sd001 (24 KB DOC)

Acknowledgments
Author contributions. TAZ, JPS, DAL, and LGK conceived the
study. TAZ and JPS obtained protocol information and execution
data. TAZ, DAL, and LGK analyzed the data and published literature.
DAL, LW, and RW provided clinical insights. TAZ, JPS, and FLM
provided historical perspectives and references. All authors contributed to writing and editing the manuscript.
References
1. Denno D (2002) When legislatures delegate death: The troubling paradox
behind state uses of electrocution and lethal injection and what it says
about us. Ohio State Law Journal 63: 63–260. Available at: http://moritzlaw.
osu.edu/lawjournal/issues/volume63/number1/denno.pdf. Accessed 16
March 2007.
2. Fellner J, Tofte S (2006) So long as they die: Lethal injection in the United
States. Human Rights Watch. Available at: http://hrw.org/reports/2006/
us0406. Accessed 16 March 2007.
3. Oklahoma Statute Title §22–1014(A) Available at: http://www.lsb.state.ok.us/
osstatuestitle.html. Accessed 16 March 2007.
4. United States District Court, Western District of Oklahoma (20 July 2005)
Complaint and Motion to Dismiss, Anderson v. Evans. Case Number 5–825.
Document Number 1, pp. 25–34.
5. US District Court, Western District of Oklahoma (6 September 2005)
Complaint and Motion to Dismiss, Anderson v. Evans. Case Number 5–825.
Document Number 26, pp. 3–4.
6. Dundee JW (1960) Alterations in response to somatic pain associated with
anaesthesia. II. The effect of thiopentone and pentobarbitone. Br J Anaesth
32: 407–414.
7. Koniaris LG, Zimmers TA, Lubarsky DA, Sheldon JP (2005) Inadequate
anaesthesia in lethal injection for execution. Lancet 365: 1412–1414.

0651

April 2007 | Volume 4 | Issue 4 | e156

Lethal Injection for Execution
8. North Carolina Department of Correction (2007) News regarding
scheduled executions. Available at: http://www.doc.state.nc.us/dop/
deathpenalty/execution_news.htm. Accessed: 19 March 2007.
9. United States District Court, Northern District of California (20 January
2006) Exhibit A to Motion for TRO, Morales v. Hickman. Case Number 6–
219. San Quentin Operational Procedure No. 770. Available at: http://www.
law.berkeley.edu/clinics/dpclinic/Lethal%20Injection%20Documents/
California/Morales/Morales%20Dist%20Ct.Cp/Ex%20A%20to%20TRO%
20motion%20(Procedure%20No.%20770).pdf. Accessed 16 March 2007.
10. United States District Court, Northern District of California (20 January
2006) Exhibit 2 to Exhibit C in Motion for TRO, Morales v. Hickman. Case
Number 6–219. Document Number 15–2. Available at: http://www.law.
berkeley.edu/clinics/dpclinic/Lethal%20Injection%20Resource%20Pages/
resources.ca.html. Accessed 16 March 2007.
11. United States Supreme Court (6 March 2007) Brief for Amicus Habeas
Corpus Resource Center, Hill v. McDonough. Case Number 05–8794.
Available at: http://www.law.berkeley.edu/clinics/dpclinic/Lethal%
20Injection%20Documents/Florida/Hill/2006.03.06%20amicus%20hcrc.
pdf. Accessed 16 March 2007.
12. United States District Court, Eastern District of North Carolina (31
October 2005) Polk Deposition, Page v. Beck. Case Number 5:04-ct-4.
Document Number 98.
13. United States District Court, Eastern District of North Carolina (3
November 2005) Second Heath Affidavit, Page v. Beck. Case Number 4–
04. Document Number 102.
14. United States District Court, Eastern District of North Carolina (27
September 2004) Affidavit of Dershwitz, Perkins v. Beck. Case Number 04–
643. Document Number 7, pp. 22–31.
15. United States District Court, Eastern District of North Carolina (7 April
2006) Order, Brown v. Beck. Case Number 5:06-CT-3018-H. Available at:
http://deathpenaltyinfo.org/Brownorder.pdf. Accessed 16 March 2007.
16. United States District Court, Northern District of California (25 January
2006) Second Declaration of Dr. Mark Heath, Morales v. Hickman. Case
Number 06–219. Document Number 22–1.
17. United States District Court, Northern District of California (20 January
2006) Declaration of Patterson, Morales v. Hickman. Case Number 06–219.
Document Number 14. Available at: http://www.law.berkeley.edu/clinics/
dpclinic/Lethal%20Injection%20Documents/California/Morales/
Morales%20Dist%20Ct.Cp/Ex%20B%20to%20TRO%20Motion.pdf.
Accessed 16 March 2007.
18. United States District Court, Northern District of California
(20 January 2006) Declaration of Rocconi, Morales v. Hickman. Case
Number 06–219. Document Number 15–4. Available at : http://www.law.
berkeley.edu/clinics/dpclinic/Lethal%20Injection%20Documents/
California/Morales/Morales%20Dist%20Ct.Cp/Ex%203%20to%20Heath%
20Decl%20(Rocconi%20Decl%20re.%20Anderson%20execution).pdf.
Accessed 16 March 2007.
19. Steinbrook R (2006) New technology, old dilemma—Monitoring EEG
activity during executions. N Engl J Med 354: 2525–2527.
20. Abbott Laboratories (1993 November) Pentothal for injection, USP
(Thiopental Sodium) Reference 06–8965-R10. A similar document is
available at: http://www.rxlist.com/cgi/generic/thiopental.htm. Accessed 16
March 2007.
21. Werner HW, Pratt TW, Tatum AL (1937) A comparative study of several
ultrashort-acting barbiturates, nembutal, and tribromethanol. J Pharmacol
Exp Ther 60: 189–197.
22. Robinson MH (1945) The effect of different injection rates on upon the
AD50, LD50 and anesthetic duration of pentothal in mice, and strengthduration curves of depression. J Pharmacol Exp Ther 85: 176–191.
23. (1994) Administration and compounding of euthanasic agents. The Hague:
Royal Dutch Society for the Advancement of Pharmacy.
24. United States District Court, Northern District of California (20 January
2006) Declaration of Dershwitz, Morales v. Woodford. Case Number 06–
219. Document Number 15.
25. Harris WH (1943) Collapse under pentothal sodium. Lancet 242: 173–174.
26. Taylor JD, Richards RK, Tabern DL (1951) Metabolism of 35S thiopental
(pentothal): Chemical and paper chromatographic studies of 35S excretion
by the rat and monkey. J Pharmacol Exp Ther 104: 93–102.
27. (2005) Freedom of Information Summary. Original Abbreviated New
Animal Drug Application. Euthanasia-III Solution. Rockville (Maryland):

PLoS Medicine | www.plosmedicine.org

28.

29.

30.

31.

32.

33.
34.
35.
36.
37.
38.

39.

40.
41.

42.
43.
44.

45.

46.
47.

48.

49.

0652

Food and Drug Administration. Available at: http://www.fda.gov/cvm/FOI/
200–280020305.pdf. Accessed 6 March 2007.
Wetherton AR, Corey TS, Buchino JJ, Burrows AM (2003) Fatal intravenous
injection of potassium in hospitalized patients. Am J Forensic Med Pathol
24: 128–131.
Gensia Sicor Pharmaceuticals (2003 October) Pancuronium bromide
injection (prescribing information and material safety data sheet).
Available at: http://www.sicor.com/products/1044.html. Accessed 16 March
2007.
Mehta MP, Sokoll MD, Gergis SD (1988) Accelerated onset of nondepolarizing neuromuscular blocking drugs: Pancuronium, atracurium and
vecuronium. A comparison with succinylcholine. Eur J Anaesthesiol 5: 15–
21.
Tisch C, Krueger C (14 December 2006) Second dose needed to kill inmate.
St Petersburg Times. State/Suncoast edition. St. Petersburg. p. 1A. Available
at: http://www.sptimes.com/2006/12/14/State/Second_dose_needed_to.
shtml. Accessed 16 March 2007.
United States Supreme Court (6 March 2006) Brief for Amicus Curiae,
Darick Demorris Walker, Hill v. McDonough. Case Number 05–8794.
Available at: http://www.jenner.com/files/tbl_s69NewsDocumentOrder/
FileUpload500/674/Brief_Amicus_Curiae_Walker.pdf. Accessed 16
March 2007.
Brodie BB, Mark LC, Lief PA, Bernstein E, Papper EM (1951) Acute
tolerance to thiopental. J Pharmacol Exp Ther 102: 215–218.
Heard KM (1936) Pentothal: A new intravenous anesthetic. Can Med Assn J
34: 628–634.
Mallison FB (1937) Pentothal sodium in intravenous anaesthesia. Lancet
230: 1070–1073.
Kohn DF, Wixson SK, White WJ, Benson GJ, editors (1997) Anesthesia and
analgesia in laboratory animals. New York: Academic Press. 426 p.
Plumb DC (2005) Veterinary drug handbook. 5th Ed. Stockholm (Wisconsin): PharmaVet. 929 p.
Mordenti J, Chappell W (1989) The use of interspecies scaling in
toxicokinetics. In: Yacobi A, Kelly J, Batra V, editors. Toxicokinetics and
new drug development. New York: Pergamon Press. pp. 42–96.
Center for Drug Evaluation and Research (2005) Guidance for industry
estimating the maximum safe starting dose in initial clinical trials for
therapeutics in adult healthy volunteers. Rockville (Maryland): Food and
Drug Administration. Available at: http://www.fda.gov/CDER/GUIDANCE/
5541fnl.htm. Accessed 16 March 2007.
Hannon JP, Bossone CA, Wade CE (1990) Normal physiological values for
conscious pigs used in biomedical research. Lab Anim Sci 40: 293–298.
United States District Court, Northern District of California (15 February
2006) Memorandum of Intended Decision; Request for Response from
Defendants, Morales v. Tilton. Case Number C 06–219, C 06–926. Available
at: http://www.deathpenaltyinfo.org/CalifLethalInjection.pdf. Accessed 16
March 2007.
Koniaris LG, Sheldon JP, Zimmers TA (2007) Can lethal injection for
execution really be ‘‘fixed’’? Lancet 369: 352–353.
Mirsky JH, Giarman NJ (1955) Studies on the potentiation of thiopental. J
Pharmacol Exp Ther 114: 240–249.
Richards RK, Taylor JD, Kueter KE (1953) Effect of nephrectomy on the
duration of sleep following administration of thiopental and hexobarbital.
J Pharmacol Exp Ther 108: 461–473.
Gruber CM, Gruber JCM, Colosi N (1937) The effects of anesthetic doses of
sodium thio-pentobarbital, sodium thio-ethamyl and pentothal sodium
upon the respiratory system, the heart and blood pressure in experimental
animals. J Pharmacol Exp Ther 60: 143–147.
Ramsey H, Haag HB (1946) The synergism between the barbiturates and
ethyl alcohol. J Pharmacol Exp Ther 88: 313–322.
Wyngaarden JB, Woods LA, Ridley R, Seevers MH (1948) Anesthetic
properties of sodium 5-allyl-5-(1-methyl-butyl)-2-thiobarbiturate (surital)
and certain other thiobarbiturates in dogs. J Pharmacol Exp Ther 95: 322–
327.
Sharma RP, Stowe CM, Good AL (1970) Studies on the distribution and
metabolism of thiopental in cattle, sheep, goats and swine. J Pharmacol Exp
Ther 172: 128–137.
Komar E (1991) Intravenous anaesthesia in the sheep. Proc Int Congr Vet
Anesth, 4th. Utrecht (The Netherlands). pp. 209–210.

April 2007 | Volume 4 | Issue 4 | e156

Lethal Injection for Execution

Editors’ Summary
Background. Lethal injection is a common form of execution in a
number of countries, most prominently the US and China. The protocols
currently used in the US contain three drugs: an ultrashort-acting
barbiturate, thiopental (which acts as an anesthetic, but does not have
any analgesic effect); a neuromuscular blocker, pancuronium bromide
(which causes muscle paralysis); and an electrolyte, potassium chloride
(which stops the heart from beating). Each of these drugs on its own was
apparently intended by those who derived the protocols to be sufficient
to cause death; the combination was intended to produce anesthesia
then death due to respiratory and cardiac arrest. Following a number of
executions in the US, however, it has recently become apparent that the
regimen as currently administered does not work as efficiently as
intended. Some prisoners take many minutes to die, and others become
very distressed.

duration of the execution, and that potassium chloride does not reliably
induce cardiac arrest. They conclude therefore that potentially aware
inmates could die through asphyxiation induced by the muscle paralysis
caused by pancuronium.
What Do These Findings Mean? The authors conclude that even if
lethal injection is administered without technical error, those executed
may experience suffocation, and therefore that ‘‘the conventional view
of lethal injection as an invariably peaceful and painless death is
questionable.’’ The Eighth Amendment of the US Constitution prohibits
cruel and unusual punishment. The results of this paper suggest that
current protocols used for lethal injection in the US probably violate this
amendment.
Additional Information. Please access these Web sites via the online
version of this summary at http://dx.doi.org/10.1371/journal.pmed.
0040156.

Why Was This Study Done? It is possible that one cause of these
difficulties with the injections is that the staff administering the drugs are
not sufficiently competent; doctors and nurses in the US are banned by
their professional organizations from participating in executions and
hence most personnel have little medical knowledge or skill. Alternatively, the drug regimens used might not be effective; it is not clear
whether they were derived in any rational way. The researchers here
wanted to investigate the scientific basis for the protocols used.

 In a linked editorial the PLoS Medicine editors discuss this paper further
and call for the abolition of the death penalty
 The Death Penalty Information Center is a rich resource on the death
penalty both in the US and internationally
 Information on challenges to lethal injection in various states,
including California and North Carolina, is available from the University
of California, Berkeley School of Law
 Human Rights Watch monitors executions in the US
 Amnesty International campaigns against the death penalty
 A compendium of death penalty-related links are available from a prodeath-penalty site, the Clark County Prosecuting Attorney

What Did the Researchers Do and Find? They analyzed data from
some of the few states (North Carolina and California) that release
information on executions. They also assessed the regimens with respect
to published data from clinical, laboratory, and veterinary animal studies.
The authors concluded that in the current regimen thiopental might not
be fatal and might be insufficient to induce surgical anesthesia for the

PLoS Medicine | www.plosmedicine.org

0653

April 2007 | Volume 4 | Issue 4 | e156