ARTICLE IN PRESS
PAINÒ xxx (2009) xxx–xxx
www.elsevier.com/locate/pain
Commentary
Blood sampling and other needle procedures – The Achilles heel of newborn
intensive care
Critical illness and trauma can accelerate the generation of reac- Then, it is plausible that babies who required more heel massage
tive oxygen free radicals (FR), which can harm many tissues. The experienced more severe pain, had more local tissue trauma, and
newborn may be particularly vulnerable to oxidative injury. In had greater increases in AOPP and TH due to local, rather than sys-
the current issue of Pain, Bellieni et al. [1] measured advanced oxy- temic, generation of FR. It would support the ‘‘local oxidation”
gen protein products (AOPP) and total hydroperoxides (TH) as sur- hypothesis if a post hoc review showed a correlation between
rogate measures of FR generation in blood samples at the potassium measurements and either baseline values or heel mas-
beginning and end of diagnostic heel lancing procedures in new- sage-evoked increases in AOPP and TH.
borns. For the subset of babies with the highest behavioral pain These two interpretations could be tested by further experi-
scores, concentrations of AOPP and TH increased between blood ments involving simultaneous central venous sampling from ba-
samples taken at the end, compared to the beginning, of the heel bies with indwelling lines who nevertheless require heelstick
lance. Their two primary conclusions are: (1) pain can accelerate sampling or who could have repeated sampling of drops of blood
FR generation in newborns, and (2) since FR can harm organs, cli- from operative sites during surgery. Anti-inflammatory effects of
nicians should consider ‘‘use of effective analgesic procedures for local anesthetics are complex, and could confound these
every type of potentially painful event, in order to avoid the dan- measurements.
gerous effects of oxidative stress” [1]. In this Commentary, we con- Although Bellieni et al. [1] showed statistically significant in-
sider aspects of the design, results, and conclusions of the Bellieni creases in the values for AOPP and TH for this subgroup, the effect
et al. study [1] and some general problems with physiologic sizes for these increases are relatively small, and of unknown clin-
parameters as sole indicators of pain in critically ill neonates [2]. ical significance.
Newborns in Neonatal Intensive Care Units (NICUs) are sub- Effect sizes and clinical significance are pertinent to the authors’
jected to repeated noxious events, including, but not limited to, re- second conclusion; namely, that analgesics should be provided for
peated needle procedures. In sick newborns, frequent laboratory every potentially painful procedure. Interventions such as posi-
tests provide crucial information to guide physiologic interven- tioning and nesting, use of non-nutritive sucking (e.g. pacifiers),
tions. Blood sampling is, therefore, a necessary, though noxious, as- kangaroo mother care [5], breastfeeding [8] and oral sucrose [10]
pect of newborn intensive care. Heel lancing has long been used for have been shown to have clearly measurable (although often
blood sampling for babies who lack vascular access. While heel incomplete) efficacy and minimal risk. Our recommendation is to
lancing is technically simple, it produces tissue trauma, hyperalge- use these non-pharmacologic interventions to ameliorate the ef-
sia [12], and behavioral and physiologic activation indicative of fects of heel lances whenever possible.
pain especially with repeated heel lances, which produce bruising Conversely, topical local anesthetics, acetaminophen, and mor-
and inflammation. phine have been ineffective as analgesics in clinical trials for heel
Blood sampling relies on the assumption that the sample re- lancing [4,6,9], and we were unable to identify published NSAID
flects systemic physiology. For example, measured serum or plasma trials. Infant rats show diminished analgesic responses to cycloox-
sodium concentrations are similar from arterial, venous or heel- ygenase inhibition compared to older animals [7]. Opioid tolerance
lance sources. Other measurements (e.g. the partial pressure of proceeds more rapidly in younger animals and humans compared
oxygen) differ markedly from different sites. Heel lancing is irre- to older ones. It remains unclear whether any currently-available
producible, and squeezing the heel repeatedly is often required analgesic medication has a definable risk–benefit ratio for reducing
to get sufficient blood for sampling. Heel lance blood samples, pain or oxidative stress from heel lancing in neonates. Future study
therefore, can be influenced by local injury and hemolysis. For of both pharmacologic and non-pharmacologic interventions
example, heel lancing is notorious for generating falsely elevated should evaluate effects of interventions on immediate behaviors,
potassium measurements. stress responses, and hyperalgesia [12].
Bellieni et al. [1] regard the observed increases in AOPP and TH Nevertheless, heel lancing is clearly painful and stressful, and
as markers for a systemic oxidative response to pain. While they alternatives to this procedure should be sought. Non-invasive
may be correct, an alternative hypothesis is that these increases methods for physiologic measurement, most notably pulse oxime-
could reflect local oxidative responses to the injury of heel lancing. try and exhaled breath capnometry have clearly reduced pain and
Suppose that, in general, heel lancings that require more massag- distress for countless infants, and have greatly refined mechanical
ing of the heel are more traumatic to tissues and more painful. ventilation and adjustment of inspired oxygen concentrations.
Breath analysis has a growing range of applications, including
DOI of original article: 10.1016/j.pain.2009.08.025 metabolic studies.
0304-3959/$36.00 Ó 2009 Published by Elsevier B.V. on behalf of International Association for the Study of Pain.
doi:10.1016/j.pain.2009.09.005

ARTICLE IN PRESS
2 Commentary / PAINÒ xxx (2009) xxx–xxx
Physiologic indicators are problematic as sole measures of acute [4] Carbajal R, Lenclen R, Jugie M, Paupe A, Barton BA, Anand KJS. Morphine does
not provide adequate analgesia for acute procedural pain among preterm
pain in infants; many other nonpainful processes evoke sympa-
neonates. Pediatrics 2005;115:1494–500.
thetic activation and stress responses [2]. Conversely, repetitive [5] Johnston CC, Filion F, Campbell-Yeo M, Goulet C, Bell L, McNaughton K, Byron J.
stress can be harmful per se, independent of subjective distress. Enhanced kangaroo mother care for heel lance in preterm neonates: a
It is therefore appropriate to assess physiological indicators along crossover trial. J Perinatol 2009;29:51–6.
[6] O’Brien L, Taddio A, Lyszliewicz DA, Koren G. A critical review of the topical
with behavioral indicators in response to noxious events such as local anesthetic amethocaine (Ametop) for pediatric pain. Pediatric Drugs
heel lance. This approach underlies the ever-expanding repository 2005;7:41–5.
of composite infant pain measures such as the PIPP [11] which de- [7] Ririe DG, Prout HM, Eisenach JC. Effect of cyclooxygenase-1 inhibition in
postoperative pain is developmentally regulated. Anesthesiology
tect multiple dimensions of pain and contextual factors that affect 2004;101:1031–5.
expression of pain. [8] Shah PS, Aliwalas LL, Shah VS. Breastfeeding or breast milk for procedural pain
There is a lack of high quality evidence for the efficacy, effec- in neonates. Cochrane Database Syst Rev 2006;3:CD00495.
[9] Shah V, Taddio A, Ohlsson A. Randomised controlled trial of paracetamol for
tiveness or cost–benefit of standardized pain assessment in rela- heel prick pain in neonates. Arch Dis Child Fetal Neonatal Ed
tion to clinical or process outcomes in pediatrics. 1998;79:209F–11F.
In the NICU, where neonates undergo an average of approxi- [10] Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn infants
undergoing painful procedures. Cochrane Database Syst Rev
mately 10 painful procedures per day [3], clinicians and research- 2004;3:CD001069.
ers must work simultaneously on implementing evidence-based [11] Stevens B, Johnston C, Petryshen P, Taddio A. Premature infant pain profile:
management strategies [13] while seeking more objective physio- development and initial validation. Clin J Pain 1996;12:13–22.
[12] Taddio A, Shah V, Atenafu E, Katz J. Influence of repeated painful procedures
logic or behavioral pain indicators. System-wide approaches aimed
and sucrose analgesia on the development of hyperalgesia in newborn infants.
at pain prevention should include optimal use of non-invasive Pain 2009;144:43–8.
methods of physiologic monitoring, improved clinical decision pro- [13] Yamada J, Stinson J, Lamba J, Dickson A, McGrath PJ, Stevens B. A review of
cedures to prevent unnecessary or redundant blood sampling, and systematic reviews on pain interventions in hospitalized infants. Pain Res
Manag 2008;13:413–20.
avoidance of heel lancing when alternative sampling methods are
available.
Charles B. Berde
Harvard Medical School, Boston, MA, USA
Acknowledgments Division of Pain Medicine, Department of Anesthesiology, Perioperative
and Pain Medicine, Children’s Hospital Boston, 333 Longwood Avenue,
Supported by the Sara Page Mayo Endowment for Pediatric Pain Room 555, Boston, MA 02115, USA
Research and Treatment. Tel.: +1 617 355 7040; fax: +1 617 812 3089.
Ms. Elizabeth Carpino provided expert assistance in the prepa- E-mail address: charles.berde@childrens.harvard.edu
ration of this manuscript.
Bonnie Stevens
Lawrence S. Bloomberg Faculty of Nursing & Faculty of Medicine,
References University of Toronto, Toronto, Ont., Canada
[1] Bellieni CV, Iantorno L, Perrone S, Rodriguez A, Longini M, Capitani S,
Research Institute, The Hospital for Sick Children, 555 University Ave.,
Buonocore G. Even routine painful procedures can be harmful for the Room 4734b Toronto, Ont., Canada M5G 1X8
newborn. Pain 2009. doi:10.1016/j.pain.2009.08.025. Tel.: +1 416 813 6595; fax: +1 416 813 8273.
[2] Berde CB, McGrath PJ. Pain measurement and Beecher’s challenge, 50 years
E-mail addresses: b.stevens@utoronto.ca
later. Anesthesiology 2009;111:473–4.
[3] Carbajal R, Rousset A, Danan C, Coquery S, Nolent P, Ducrocq S, Saizou C, Received 24 August 2009
Lapillone A, Granier M, Durand P, Lenclen R, Coursol A, Hubert P, de Saint Received in revised form 30 August 2009
Blanquat L, Boelle P, Annequin D, Cimerman P, Anand KJS, Breart G.
Epidemiology and treatment of painful procedures in neonates in intensive
care units. JAMA 2008;300:60–70.4. Available online xxxx