Professional Documents
Culture Documents
Dr. Andrew S. Hoekzema (Medicine): An 83-year-old woman was admitted to this From the Departments of Medicine
hospital in the winter because of nausea, vomiting, diarrhea, and confusion. (M.L.P.M., L.H.S.), Radiology (V.V.M.), Car-
diology (C.N.-C.), and Pathology (R.K.C.),
One week before admission, rhinorrhea, sore throat, and nonproductive cough Massachusetts General Hospital, and the
developed. The patient felt feverish but did not measure her temperature at home. Departments of Medicine (M.L.P.M.,
No family members or recent contacts had been ill. Two days before admission, L.H.S.), Radiology (V.V.M.), Cardiology
(C.N.-C.), and Pathology (R.K.C.), Harvard
nausea, vomiting, and diarrhea developed. One day before admission, the patient Medical School — both in Boston.
asked her daughter repetitive questions and appeared to not recognize family
N Engl J Med 2018;378:1931-8.
members. On the day of admission, the patient reported global weakness and was DOI: 10.1056/NEJMcpc1800339
brought by her daughter to the emergency department of this hospital for evaluation. Copyright © 2018 Massachusetts Medical Society.
Delirium
The diagnosis of delirium in this patient is a
cause for alarm, since delirium is associated B
with increased mortality during hospitalization4,5
and at 1 year after diagnosis.6 The most impor-
tant step after the recognition of delirium is to
identify the underlying cause, which involves con-
sideration of common reversible conditions that
have been described in hospitalized older adults.7
Drugs
Medications are a common cause of delirium,
particularly in older adults. Although this patient
was receiving warfarin, her international normal-
ized ratio was almost always in the therapeutic
range, indicating that she had adhered to the
prescription and seemed to have taken the medi-
cation correctly. Although psychoactive drugs had
not been prescribed in the patient, she took mul-
tiple medications — including anticoagulants,
diuretics, and several cardiac medications —
that increased her risk of adverse drug events.
Withdrawal syndromes can cause delirium, but Figure 1. Chest Radiographs.
this patient did not drink alcohol or use medica- Posteroanterior and lateral chest radiographs (Panels A
tions, such as benzodiazepines, that are associ- and B, respectively) show evidence of marked cardio-
ated with withdrawal syndromes. However, it megaly, with a cardiothoracic ratio of more than 80%,
and mild interstitial pulmonary edema.
remains possible that a drug effect could have
contributed to her delirium.
Electrolyte and Metabolic Disturbances tion. Taken together, these findings are suggestive
This patient’s calcium level is not reported, but of volume depletion. I suspect her hyponatremia
she had mild hyponatremia and her urinalysis was due to an inadequate effective arterial blood
was notable for the presence of ketones. On volume, leading to the ongoing release of anti-
physical examination, she had dry mucous mem- diuretic hormone. The hyponatremia was not
branes and no leg edema or jugular venous disten- severe enough to fully explain her delirium, but
it can be a marker of underlying volume deple- per respiratory infection. Tests for influenza A
tion, which can contribute to delirium. and B viruses and respiratory syncytial virus were
This patient’s glucose level was normal. The negative, but other influenza-like illnesses remain
thyrotropin level is not available, but she did not possible. More remotely acquired infections, such
have symptoms that were suggestive of either as human immunodeficiency virus and Mycobac-
hypothyroidism or hyperthyroidism. The combi- terium tuberculosis infections, are also possible in
nation of hyponatremia, hyperkalemia, and glob- this patient who had emigrated from Uganda 19
al weakness can indicate adrenal insufficiency, a years before admission. Weight loss is not re-
very uncommon cause of delirium that may also ported, but she was described as being cachectic
explain the nausea, vomiting, and fatigue. How- and she had a BMI of 18.7 (with values of <18.5
ever, the absence of hypotension makes adrenal indicating underweight status).8 However, she
insufficiency unlikely. had normally walked for 30 minutes daily, indi-
cating that she was physically robust, so perhaps
Cardiopulmonary Disorders she was just a very thin person.
Cardiac and pulmonary disorders can lead to
delirium through hypoxemia or hypercarbia. Al- Narrowing the Differential Diagnosis
though I do not have access to results of tests of Can any features of this case help us to deter-
arterial blood gases for this patient, there is no mine the most likely diagnosis? The most striking
history of lung disease that would raise suspi- laboratory finding is the blood creatinine level
cion for these abnormalities. In addition, I have of 1.6 mg per deciliter (141 μmol per liter), which
not seen the results of electrocardiography for had increased from a baseline level of 1.2 mg
this patient, but she did not report chest pain per deciliter and is consistent with acute kidney
and she had a normal troponin T level, and these injury. However, despite the normal baseline
findings make myocardial infarction unlikely. She blood creatinine level, this patient also had chron-
had evidence of rales on pulmonary auscultation, ic kidney disease with a reduced estimated GFR.
mild pulmonary vascular congestion on chest The GFR decreases naturally with age, even
radiography, and an elevated level of N-terminal in the absence of renal disease, with a 35% de-
pro–B-type natriuretic peptide, findings that crease between 20 years and 70 years of age.9,10
indicate a component of congestive heart failure. Estimating the GFR is difficult, particularly in
However, her oxygen saturation was normal, people with an older age, low muscle mass, or a
and thus it is unlikely that a cardiac or pulmo- low-protein diet.10 Because creatinine comes from
nary process would be the main driver of her muscle, people with lower muscle mass should
delirium. normally have a lower blood creatinine level. In
this patient, the baseline estimated GFR accord-
Infection ing to the MDRD formula was 50 ml per minute
Infection involving the central nervous system is per 1.73 m2, a finding consistent with stage 3A
a serious consideration in patients with delirium, chronic kidney disease. However, this estimated
especially those with an abnormal neurologic GFR is inaccurate, since the MDRD formula as-
examination or with no more likely cause of the sumes a body-surface area of 1.73 m2. Because
condition. It is reassuring that this patient’s neu- this patient weighed 39.2 kg, she would need to be
rologic examination was unremarkable and that more than 7 ft (2.15 m) tall to have a body-surface
the history did not raise concerns about seizure area of 1.73 m2. She had a BMI of 18.7 and a
activity. In addition, non–contrast-enhanced CT height of 4 ft 9 in. (1.45 m), and she most likely
of the head revealed only prominent ventricles had a very low muscle mass. The Cockcroft–Gault
and nonspecific periventricular white-matter hypo equation can also be used to calculate creatinine
densities. clearance in estimating the GFR. This equation
Infections outside the central nervous system takes weight into account and can be helpful in
can also lead to delirium. Two common culprits, patients whose weight is extremely low. Accord-
urinary tract infection and pneumonia, are un- ing to the Cockcroft–Gault equation, this patient’s
likely in the absence of pyuria and of consolida- baseline creatinine clearance was 22 ml per min-
tion on chest radiography, respectively. Although ute, indicating stage 4 chronic kidney disease.
this patient had no known sick contacts, she The combination of chronic kidney disease,
presented in the winter after she had had an up- acute renal failure, and older age increases this
patient’s risk of adverse drug events. Adverse drug ters that she had been doing well at home until
events are common, occurring in at least 5% of this sudden decline and that they thought she
hospitalized patients,11,12 and they are more com- had a viral illness. I was especially concerned,
mon among patients in the outpatient setting. because the patient rarely sought medical atten-
Medications that commonly cause adverse events tion for illnesses. During my initial assessment
include oral hypoglycemic agents, oral anticoagu- in the emergency department, I thought a viral
lants, antiplatelet drugs, and opiates. This patient illness could have precipitated heart failure or
was taking spironolactone, which is contraindi- renal failure. However, her confusion was the
cated in patients older than 65 years who have a most worrisome feature of her presentation, and
creatinine clearance of less than 35 ml per min- it prompted me to consider the possibility of di-
ute and is associated with ataxia, confusion, goxin toxicity and to request a digoxin immuno-
lethargy, hyperkalemia, nausea, vomiting, diar- assay.
rhea, and acute kidney injury.13 Another possible
cause of this patient’s condition is digoxin toxic- Cl inic a l Di agnosis
ity, which is characterized by confusion, dizziness,
nausea, vomiting, diarrhea, weakness, and visual Digoxin toxicity.
disturbances.14 The major route of elimination of
digoxin is through renal excretion, and the blood Dr . Mel iss a L .P. M at t ison’s
level of digoxin can rise in the context of a re- Di agnosis
duced GFR. Approximately 20 to 30% of digoxin
is bound to blood albumin, and factors such as Delirium due to an adverse event related to di-
older age, congestive heart failure, and renal goxin and possibly spironolactone.
failure reduce the volume of distribution, contrib-
uting to an increased risk of toxic effects. Di agnos t ic Te s t ing
This patient did not have the ataxia that is
associated with spironolactone toxicity or the Dr. Rory K. Crotty: The diagnostic test in this case
visual disturbances that are associated with was a digoxin immunoassay. Testing of a blood
digoxin toxicity, but otherwise, the features of sample obtained in the emergency department
her presentation fit well with both conditions. revealed a digoxin level of 9.0 ng per milliliter
Therefore, drug toxicity, probably from digoxin, (therapeutic range, 0.9 to 2.0). The international
is the most likely diagnosis in this case. I sus- normalized ratio was more than 16.
pect the diagnostic test was an immunoassay to The digoxin level is frequently monitored be-
determine the blood digoxin level. cause of the narrow therapeutic range and the
Dr. Meridale Baggett (Medicine): Dr. Simmons, potential for serious adverse drug events. This
what was your clinical impression when you patient was also taking spironolactone, which
initially evaluated this patient? has historically been reported to interfere with
Dr. Leigh H. Simmons: This patient had been testing of the digoxin level by acting as a digoxin-
under my care for several years, but I saw her in like immunoreactive substance. The term digoxin-
the office very infrequently after she lost Medic- like immunoreactive substance encompasses a
aid coverage, which was not reinstated for unclear broad range of substances, both exogenous and
reasons. Despite our requests that her family endogenous in origin, that may interfere with
bring her in for routine checks and for assis- digoxin immunoassays.14 Endogenous digoxin-like
tance with exploring options for health insurance, immunoreactive substances may be found in pa-
her family declined to do so because of concerns tients with volume expansion and appear to have
about the cost of medical visits. Through our natriuretic effects. Exogenous digoxin-like immu-
anticoagulation-management service, her inter- noreactive substances include spironolactone, can-
national normalized ratio was checked regularly renone, and Chinese herbal medications. How-
and was nearly always in the therapeutic range. ever, spironolactone and related medications are
Her family consistently refilled her medicines, not known to cause interference with the current
which were available in generic form and were generation of digoxin immunoassays that are
relatively inexpensive. used at this hospital.
When the patient presented to the emergency In cases in which the desired diagnostic test
department, I learned from her attentive daugh- is a digoxin immunoassay, a blood sample must
I aVR V1 V4
II aVL
V2 V5
III aVF V6
V3
V1
Figure 2. Electrocardiogram.
An electrocardiogram, obtained on admission, shows an underlying rhythm of atrial fibrillation with ventricular-de-
mand pacing at a rate of 60 beats per minute. When atrioventricular conduction is present, at a rate slightly higher
than 60 beats per minute, there is evidence of a regularized ventricular response with a pattern of right bundle-
branch block.
have health insurance. Patients who regain insur- excess of digoxin, but the ST-segment changes
ance after being previously uninsured start to were more consistent with the underlying con-
use outpatient services more often (as this pa- duction-system disease than with classic digoxin
tient did). Studies suggest that there are mortal- toxicity. After digoxin immune Fab was admin-
ity benefits from acquiring health insurance.18 istered, the patient was less dependent on the
For me, the particularly distressing component pacemaker; the cardiac rhythm was more irregu-
of this patient’s story is that she had survived a lar and the delay in the conduction system was
complex cardiac operation and had undergone less marked. In this case, the diagnosis of di-
advanced cardiac procedures, including pace- goxin toxicity was based on the clinical features
maker placement, only to subsequently lose ac- of an electrolyte disorder, acute renal insuffi-
cess to her regular health coverage. Routine visits ciency, and the suspected inadvertent adminis-
for primary care before this admission might tration of an excess of digoxin rather than on
have resulted in conversations about her cogni- the development of classic findings on electro-
tive functioning and her ability to manage medi- cardiography.
cines on her own, as well as a review of essential
medications and perhaps the discontinuation of Fina l Di agnosis
higher-risk medications, such as digoxin.
A Physician: What did this patient’s initial elec- Digoxin toxicity.
trocardiogram show?
This case was presented at the Internal Medicine Case Con-
Dr. Randall M. Zusman (Cardiology): I cared for ference.
this patient at the hospital. The electrocardio- Dr. Newton-Cheh reports receiving consulting fees from
gram obtained on admission (Fig. 2) showed Novartis and Ironwood and consulting fees and advisory board
fees from GE Healthcare. No other potential conflict of inter-
an underlying rhythm of atrial fibrillation with est relevant to this article was reported.
ventricular-demand pacing at a rate of 60 beats Disclosure forms provided by the authors are available with
per minute. When atrioventricular conduction the full text of this article at NEJM.org.
We thank Dr. James Flood for guidance on testing for digoxin
was present, there was evidence of a regularized and Dr. Andrew Fenves for guidance on the nuances of renal-
ventricular response that was consistent with an function testing.
References
1. Gilmore EJ, Gaspard N, Choi HA, 7. Marcantonio ER. Delirium in hospi- tone. September 17, 2007 (https://toxnet
et al. Acute brain failure in severe sepsis: talized older adults. N Engl J Med 2017; .nlm.nih.gov/cgi-bin/sis/search/
a prospective study in the medical inten- 377:1456-66. a?dbs+hsdb:@term+@DOCNO+3184).
sive care unit utilizing continuous EEG 8. Centers for Disease Control and Pre- 14. Dasgupta A. Therapeutic drug monitor-
monitoring. Intensive Care Med 2015;41: vention. About adult BMI. August 29, 2017 ing of digoxin: impact of endogenous and
686-94. (https://w ww.cdc.gov/healthyweight/ exogenous digoxin-like immunoreactive
2. Maldonado JR. Acute brain failure: assessing/bmi/adult_bmi/index.html). substances. Toxicol Rev 2006;25:273-81.
pathophysiology, diagnosis, management, 9. Coresh J, Astor BC, Greene T, Eknoyan 15. Withering W. An account of the fox-
and sequelae of delirium. Crit Care Clin G, Levey AS. Prevalence of chronic kidney glove, and some of its medical uses: with
2017;33:461-519. disease and decreased kidney function in practical remarks on dropsy and other dis-
3. Inouye SK, van Dyck CH, Alessi CA, the adult US population: Third National eases. Birmingham, England:M. Swinney,
Balkin S, Siegal AP, Horwitz RI. Clarify- Health and Nutrition Examination Survey. 1785.
ing confusion: the confusion assessment Am J Kidney Dis 2003;41:1-12. 16. Digitalis Investigation Group. The ef-
method: a new method for detection of 10. Frequently asked questions about GFR fect of digoxin on mortality and morbidity
delirium. Ann Intern Med 1990;113:941-8. estimates. New York:National Kidney in patients with heart failure. N Engl J Med
4. Russo A, Falcone M, Venditti M. Early Foundation, 2014. 1997;336:525-33.
identification of severe community-onset 11. Lazarou J, Pomeranz BH, Corey PN. 17. Antman EM, Wenger TL, Butler VP Jr,
pneumonia in “frail elderly patient.” Intern Incidence of adverse drug reactions in hos- Haber E, Smith TW. Treatment of 150
Emerg Med 2014;9:119-20. pitalized patients: a meta-analysis of pro- cases of life-threatening digitalis intoxi-
5. Silva TJ, Jerussalmy CS, Farfel JM, spective studies. JAMA 1998;279:1200-5. cation with digoxin-specific Fab antibody
Curiati JAE, Jacob-Filho W. Predictors of 12. Pardo Cabello AJ, González Contreras fragments: final report of a multicenter
in-hospital mortality among older patients. LG, Manzano Gamero MV, Gómez Jimé- study. Circulation 1990;81:1744-52.
Clinics (Sao Paulo) 2009;64:613-8. nez FJ, Puche Cañas E. Prevalence of fatal 18. Sommers BD, Gawande AA, Baicker K.
6. McCusker J, Cole M, Abrahamowicz adverse drug reactions in hospitalized pa- Health insurance coverage and health —
M, Primeau F, Belzile E. Delirium predicts tients. Int J Clin Pharmacol Ther 2009;47: what the recent evidence tells us. N Engl J
12-month mortality. Arch Intern Med 596-602. Med 2017;377:586-93.
2002;162:457-63. 13. Toxicology Data Network. Spironolac- Copyright © 2018 Massachusetts Medical Society.